rs1264537420

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

The NM_004304.5(ALK):c.2781G>T(p.Gly927=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G927G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000097 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALK
NM_004304.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 2-29228918-C-A is Benign according to our data. Variant chr2-29228918-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 703707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BP7

Synonymous conserved (PhyloP=2.18 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.2781G>T	p.Gly927=	synonymous_variant	16/29	ENST00000389048.8
ALK	XR_001738688.3 linkuse as main transcript	n.3668+40G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.2781G>T	p.Gly927=	synonymous_variant	16/29	1	NM_004304.5	P1
ALK	ENST00000618119.4 linkuse as main transcript	c.1650G>T	p.Gly550=	synonymous_variant	15/28	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150044

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000736

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

229678

Hom.:

AF XY:

0.00000799

AC XY:

AN XY:

125230

show subpopulations

Gnomad AFR exome

AF:

0.0000640

Gnomad AMR exome

AF:

0.0000359

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:

0.00000945

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000971

AC:

127

AN:

1307440

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

657134

show subpopulations

Gnomad4 AFR exome

AF:

0.0000329

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.000121

Gnomad4 EAS exome

AF:

0.000156

Gnomad4 SAS exome

AF:

0.000121

Gnomad4 FIN exome

AF:

0.000154

Gnomad4 NFE exome

AF:

0.0000862

Gnomad4 OTH exome

AF:

0.000127

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000267

AC:

AN:

150044

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73150

show subpopulations

Gnomad4 AFR

AF:

0.0000736

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Neuroblastoma, susceptibility to, 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2022

This alteration is classified as likely 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

-0.23

CADD

Benign

DANN

Benign

0.71

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