rs138827116

chr2-29193781-GCTC-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_004304.5(ALK):c.4303_4305del(p.Glu1435del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,593,952 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: ALK NM_004304.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.00

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]

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004304.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-29193781-GCTC-G is Benign according to our data. Variant chr2-29193781-GCTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 133471.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 = 0.005 (761/152298) while in subpopulation AFR AF= 0.0177 (735/41562). AF 95% confidence interval is 0.0166. There are 7 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 762 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.4303_4305del	p.Glu1435del	inframe_deletion	29/29	ENST00000389048.8
ALK	NM_001353765.2	c.1099_1101del	p.Glu367del	inframe_deletion	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.4303_4305del	p.Glu1435del	inframe_deletion	29/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 762 AN: 152180 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00142 AC: 333 AN: 234726 Hom.: 3 AF XY: 0.00106 AC XY: 134 AN XY: 126306

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.000525

Gnomad ASJ exome AF: 0.000242

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000374

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000653

Gnomad OTH exome AF: 0.000714

GnomAD4 exome AF: 0.000563 AC: 812 AN: 1441654 Hom.: 7 AF XY: 0.000509 AC XY: 364 AN XY: 715104

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.000800

Gnomad4 ASJ exome AF: 0.000122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000602

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152298 Hom.: 7 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74472

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00261 Hom.: 2

Bravo AF: 0.00592

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	- -

Neuroblastoma, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ALK p.Glu1435del variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138827116) and in ClinVar (classified as likely benign by EGL Genetics and Illumina and as benign by Invitae). The variant was identified in control databases in 488 of 266110 chromosomes (4 homozygous) at a frequency of 0.001834 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 456 of 24732 chromosomes (freq: 0.01844), Other in 4 of 6686 chromosomes (freq: 0.000598), Latino in 18 of 33230 chromosomes (freq: 0.000542), Ashkenazi Jewish in 2 of 8558 chromosomes (freq: 0.000234), European (non-Finnish) in 7 of 122668 chromosomes (freq: 0.000057) and South Asian in 1 of 26748 chromosomes (freq: 0.000037); it was not observed in the East Asian and European (Finnish) populations. This variant is an in-frame deletion resulting in the removal of a glutamic acid (Glu) residue at codon 1435; the impact of this alteration on ALK protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Neuroblastoma Susceptibility Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2018

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

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: rs138827116; hg19: chr2-29416647;