rs781440137

chr2-29920159-C-Achr2-29920159-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004304.5(ALK):c.501G>T(p.Gln167His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q167Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26391608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.501G>T	p.Gln167His	missense_variant	1/29	ENST00000389048.8
ALK	XR_001738688.3	n.1428G>T		non_coding_transcript_exon_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.501G>T	p.Gln167His	missense_variant	1/29	1	NM_004304.5	P1
	ENST00000669284.1	n.157+35090G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249088 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

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: 0.00000890 AC: 13 AN: 1461342 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 167 of the ALK protein (p.Gln167His). This variant is present in population databases (rs781440137, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 569680). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.59	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.024	D
Polyphen		0.93	P
Vest4		0.13
MutPred		0.68		Gain of helix (P = 0.0117);
MVP		0.67
MPC		0.24
ClinPred		0.38	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.31

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

Other links and lift over

dbSNP: rs781440137; hg19: chr2-30143025;