2-29193291-G-T

Position:

chr2-29193291-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004304.5(ALK):c.4796C>A(p.Pro1599His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 8.73

Variant links:

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ALK links:

ALK (HGNC:):

ALK links:

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

CLIP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022776932).

BP6

Variant 2-29193291-G-T is Benign according to our data. Variant chr2-29193291-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133477.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, not_provided=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000795 (121/152292) while in subpopulation AFR AF= 0.00284 (118/41562). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.4796C>A	p.Pro1599His	missense_variant	29/29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	NM_001353765.2 linkuse as main transcript	c.1592C>A	p.Pro531His	missense_variant	10/10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.4796C>A	p.Pro1599His	missense_variant	29/29	1	NM_004304.5	ENSP00000373700.3		Q9UM73

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251224

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152292

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.000842

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ALK p.Pro1599His variant was identified in 2 of 9032 proband chromosomes (frequency: 0.00022) from individuals or families with cancer, and was present in 1 of 1598 control chromosomes (frequency: 0.00063) from healthy individuals (Bodian_2014_PMID:24728327; Mandelker_2017_PMID: 28873162; Yehia_2018_PMID: 29684080). The variant was also identified in dbSNP (ID: rs1881423) and ClinVar (classified as likely benign by Invitae in 2017). The variant was not identified in the COGR, Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in control databases in 75 of 282614 chromosomes at a frequency of 0.000265 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 64 of 24968 chromosomes (freq: 0.002563), Latino in 10 of 35436 chromosomes (freq: 0.000282) and Other in 1 of 7214 chromosomes (freq: 0.000139), it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The p.Pro1599 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with advanced cancer, type not specified (Mandelker 2017); This variant is associated with the following publications: (PMID: 24728327, 31888289, 28873162) -

Neuroblastoma, susceptibility to, 3

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 31, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 26, 2024	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 24, 2021	- -

ALK-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

T;T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.90

.;L;.

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.2

.;D;.

REVEL

Benign

0.26

Sift

Uncertain

0.0010

.;D;.

Sift4G

Pathogenic

0.0010

.;D;D

Polyphen

1.0

.;D;.

Vest4

0.49, 0.49

MVP

0.40

MPC

0.71

ClinPred

0.11

GERP RS

4.8

Varity_R

0.33

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over