rs201042802

chr2-29228936-G-Achr2-29228936-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_004304.5(ALK):c.2763C>T(p.Phe921=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000164 in 499,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.85

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 2-29228936-G-A is Benign according to our data. Variant chr2-29228936-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 538277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.2763C>T	p.Phe921=	synonymous_variant	16/29	ENST00000389048.8
ALK	XR_001738688.3	n.3668+22C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.2763C>T	p.Phe921=	synonymous_variant	16/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.1632C>T	p.Phe544=	synonymous_variant	15/28	5

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 8 AN: 45068 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000672

Gnomad SAS AF: 0.00362

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000495

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 74 AN: 453882 Hom.: 0 Cov.: 14 AF XY: 0.000192 AC XY: 46 AN XY: 239714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000174

Gnomad4 ASJ exome AF: 0.000173

Gnomad4 EAS exome AF: 0.0000543

Gnomad4 SAS exome AF: 0.000454

Gnomad4 FIN exome AF: 0.000128

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000144

GnomAD4 genome AF: 0.000177 AC: 8 AN: 45154 Hom.: 0 Cov.: 0 AF XY: 0.000225 AC XY: 5 AN XY: 22250

Gnomad4 AFR AF: 0.000165

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000673

Gnomad4 SAS AF: 0.00363

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000495

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 15, 2022	- -

Neuroblastoma, susceptibility to, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	15
Dann	Benign	0.78

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: rs201042802; hg19: chr2-29451802; COSMIC: COSV101202336; COSMIC: COSV101202336;