rs756963896

Variant names:

• chr2-29233573-C-G
• NM_004304.5:c.2479G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-29233573-C-G
• chr2-29233573-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004304.5(ALK):​c.2479G>C​(p.Val827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40040195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.2479G>C	p.Val827Leu	missense_variant	Exon 14 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.3406G>C		non_coding_transcript_exon_variant	Exon 14 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.2479G>C	p.Val827Leu	missense_variant	Exon 14 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.1348G>C	p.Val450Leu	missense_variant	Exon 13 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1

Dec 01, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with leucine at codon 827 of the ALK protein (p.Val827Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.083
Sift	Benign	0.11	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.93	P;.
Vest4		0.45
MutPred		0.28		Gain of ubiquitination at K829 (P = 0.0954);.;
MVP		0.55
MPC		0.34
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.11
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-29456439;