chr2-29207278-G-GGGA

Position:

chr2-29207278-G-GGGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004304.5(ALK):c.3837-7_3837-6insTCC variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,612,734 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

ALK
NM_004304.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.81

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 Benign. Variant got -16 ACMG points.

BP6

Variant 2-29207278-G-GGGA is Benign according to our data. Variant chr2-29207278-G-GGGA is described in ClinVar as [Likely_benign]. Clinvar id is 239829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00262 (399/152308) while in subpopulation AFR AF= 0.00912 (379/41568). AF 95% confidence interval is 0.00836. There are 0 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 399 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5 linkuse as main transcript	c.3837-7_3837-6insTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2 linkuse as main transcript	c.633-7_633-6insTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 linkuse as main transcript	c.3837-7_3837-6insTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004304.5	ENSP00000373700	P1

Frequencies

GnomAD3 genomes

AF:

0.00260

AC:

395

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00905

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000677

AC:

170

AN:

250998

Hom.:

AF XY:

0.000523

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000266

AC:

389

AN:

1460426

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

726646

show subpopulations

Gnomad4 AFR exome

AF:

0.00927

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000597

GnomAD4 genome

AF:

0.00262

AC:

399

AN:

152308

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00912

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.00300

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -

Neuroblastoma, susceptibility to, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Familial isolated pituitary adenoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

May 20, 2021

The ALK c.3837-9_3837-7dup splice region change has a maximum subpopulation frequency of 0.97% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-29430144-G-GGGA?dataset=gnomad_r2_1). This population frequency exceeds the expected prevalence of a pathogenic variant causing ALK-related neuroblastic tumor susceptibility (BS1). In silico tools predict that this variant does not impact splicing (BP4). This variant been reported in >5 individuals without a personal or family history consistent with ALK-related neuroblastic tumor susceptibility (internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2023

See Variant Classification Assertion Criteria. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Sep 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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