2-181537230-G-T

Variant names:

• chr2-181537230-G-T
• rs11553356
• NM_000885.6:c.*1703G>T

Variant summary

Our verdict is Benign. The variant received -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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1703G>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*954C>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.*1703G>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*954C>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*954C>A		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1
CERKL	ENST00000409440.7	c.*954C>A		downstream_gene_variant		2		ENSP00000387080.3

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

GnomAD2 exomes AF: 0.134 AC: 17091 AN: 127790 AF XY: 0.123

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 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

African (AFR) AF: 0.227 AC: 1941 AN: 8536

American (AMR) AF: 0.211 AC: 5767 AN: 27268

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 733 AN: 10784

East Asian (EAS) AF: 0.219 AC: 2008 AN: 9164

South Asian (SAS) AF: 0.0512 AC: 3054 AN: 59642

European-Finnish (FIN) AF: 0.200 AC: 2463 AN: 12308

Middle Eastern (MID) AF: 0.0548 AC: 63 AN: 1150

European-Non Finnish (NFE) AF: 0.109 AC: 17250 AN: 158284

Other (OTH) AF: 0.122 AC: 1710 AN: 14012

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

African (AFR) AF: 0.218 AC: 9040 AN: 41380

American (AMR) AF: 0.178 AC: 2715 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 244 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1126 AN: 5160

South Asian (SAS) AF: 0.0594 AC: 286 AN: 4816

European-Finnish (FIN) AF: 0.192 AC: 2019 AN: 10536

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7426 AN: 67726

Other (OTH) AF: 0.122 AC: 257 AN: 2100

Alfa AF: 0.129 Hom.: 2323

Bravo AF: 0.155

Asia WGS AF: 0.172 AC: 598 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs11553356; hg19: chr2-182401957;