2-29193749-G-A

Position:

chr2-29193749-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000389048.8(ALK):c.4338C>T(p.Thr1446=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,598,386 control chromosomes in the GnomAD database, including 10,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1446T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 972 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9749 hom. )

Consequence

ALK
ENST00000389048.8 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.22

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:

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-29193749-G-A is Benign according to our data. Variant chr2-29193749-G-A is described in ClinVar as [Benign]. Clinvar id is 259273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29193749-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.4338C>T	p.Thr1446=	synonymous_variant	29/29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2 linkuse as main transcript	c.1134C>T	p.Thr378=	synonymous_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.4338C>T	p.Thr1446=	synonymous_variant	29/29	1	NM_004304.5	ENSP00000373700	P1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15833

AN:

152102

Hom.:

973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0871

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.0827

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.0928

AC:

22254

AN:

239714

Hom.:

1339

AF XY:

0.0933

AC XY:

12047

AN XY:

129084

show subpopulations

Gnomad AFR exome

AF:

0.0882

Gnomad AMR exome

AF:

0.0526

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.0401

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.110

AC:

158689

AN:

1446166

Hom.:

9749

Cov.:

AF XY:

0.108

AC XY:

77576

AN XY:

717514

show subpopulations

Gnomad4 AFR exome

AF:

0.0862

Gnomad4 AMR exome

AF:

0.0574

Gnomad4 ASJ exome

AF:

0.115

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.0404

Gnomad4 FIN exome

AF:

0.159

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.104

AC:

15833

AN:

152220

Hom.:

972

Cov.:

AF XY:

0.104

AC XY:

7754

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0869

Gnomad4 AMR

AF:

0.0826

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0309

Gnomad4 FIN

AF:

0.164

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.106

Alfa

AF:

0.112

Hom.:

521

Bravo

AF:

0.0978

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The c.4338C>T variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts benign outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts changes of binding motifs for splicing enhancers. This variant is found in 10961/117122 control chromosomes (649 homozygotes) at a frequency of 0.0935862, which is about 224607 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting this variant is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Squamous cell lung carcinoma

Benign:1

Likely benign, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.75

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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