chr2-181537230-G-T

Position:

• chr2-181537230-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000885.6(ITGA4):​c.*1703G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 452,766 control chromosomes in the GnomAD database, including 4,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2037 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2616 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.191

Genes affected

ITGA4 (HGNC:6140): (integrin subunit alpha 4) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 4 subunit. This subunit associates with a beta 1 or beta 7 subunit to form an integrin that may play a role in cell motility and migration. This integrin is a therapeutic target for the treatment of multiple sclerosis, Crohn's disease and inflammatory bowel disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

CERKL (HGNC:21699): (ceramide kinase like) This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-181537230-G-T is Benign according to our data. Variant chr2-181537230-G-T is described in ClinVar as [Benign]. Clinvar id is 332985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA4	NM_000885.6	c.*1703G>T		3_prime_UTR_variant	28/28	ENST00000397033.7
CERKL	NM_201548.5	c.*954C>A		3_prime_UTR_variant	13/13	ENST00000410087.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7	c.*1703G>T		3_prime_UTR_variant	28/28	1	NM_000885.6	P1
CERKL	ENST00000410087.8	c.*954C>A		3_prime_UTR_variant	13/13	1	NM_201548.5	P1
CERKL	ENST00000684145.1	c.*954C>A		3_prime_UTR_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23145 AN: 151500 Hom.: 2037 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.0704

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.134 AC: 17091 AN: 127790 Hom.: 1455 AF XY: 0.123 AC XY: 8632 AN XY: 69970

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.0705

Gnomad EAS exome AF: 0.214

Gnomad SAS exome AF: 0.0520

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.116 AC: 34989 AN: 301148 Hom.: 2616 Cov.: 0 AF XY: 0.108 AC XY: 18508 AN XY: 171668

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.0680

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.0512

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.153 AC: 23170 AN: 151618 Hom.: 2037 Cov.: 33 AF XY: 0.157 AC XY: 11601 AN XY: 74120

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.0704

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.0594

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.122

Alfa AF: 0.120 Hom.: 362

Bravo AF: 0.155

Asia WGS AF: 0.172 AC: 598 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.86
DANN	Benign	0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11553356; hg19: chr2-182401957;