rs373764155

chr2-29207278-G-GGGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.81

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 -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. This position pass quality control queck.
• BS2: High AC in GnomAd at 395 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152190 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.000523 AC XY: 71 AN XY: 135642

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.: 2 Cov.: 30 AF XY: 0.000226 AC XY: 164 AN XY: 726646

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.: 0 Cov.: 33 AF XY: 0.00248 AC XY: 185 AN XY: 74474

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.: 0

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

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
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	- -

Neuroblastoma, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373764155; hg19: chr2-29430144;