2-29228918-C-T

Variant names:

• chr2-29228918-C-T
• rs1264537420
• NM_004304.5:c.2781G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_004304.5(ALK):​c.2781G>A​(p.Gly927Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000382 in 1,307,814 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G927G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 2-29228918-C-T is Benign according to our data. Variant chr2-29228918-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 470805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.18 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.2781G>A	p.Gly927Gly	synonymous	Exon 16 of 29	NP_004295.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2781G>A	p.Gly927Gly	synonymous	Exon 16 of 29	ENSP00000373700.3
	ALK	ENST00000618119.4	TSL:5	c.1650G>A	p.Gly550Gly	synonymous	Exon 15 of 28	ENSP00000482733.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00 AC: 0 AN: 229678 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000382 AC: 5 AN: 1307814 Hom.: 0 Cov.: 22 AF XY: 0.00000152 AC XY: 1 AN XY: 657364

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30354

American (AMR) AF: 0.00 AC: 0 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24862

East Asian (EAS) AF: 0.00 AC: 0 AN: 38364

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 83028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5400

European-Non Finnish (NFE) AF: 0.00000308 AC: 3 AN: 974396

Other (OTH) AF: 0.00 AC: 0 AN: 55132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:1

Oct 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.70
PhyloP100		2.2
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1264537420; hg19: chr2-29451784;