2-181537269-G-C

Variant names:

• chr2-181537269-G-C
• rs116322351
• NM_000885.6:c.*1742G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000885.6(ITGA4):​c.*1742G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 453,592 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.019 (74 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (23 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.517

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1742G>C		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*915C>G		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.*1742G>C		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*915C>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*915C>G		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1
CERKL	ENST00000409440.7	c.*915C>G		downstream_gene_variant		2		ENSP00000387080.3

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2817 AN: 151940 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00578

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00447 AC: 572 AN: 127846 AF XY: 0.00384

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00185

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000846

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00292 AC: 879 AN: 301534 Hom.: 23 Cov.: 0 AF XY: 0.00244 AC XY: 419 AN XY: 171842

African (AFR) AF: 0.0654 AC: 559 AN: 8548

American (AMR) AF: 0.00356 AC: 97 AN: 27264

Ashkenazi Jewish (ASJ) AF: 0.00213 AC: 23 AN: 10784

East Asian (EAS) AF: 0.00 AC: 0 AN: 9150

South Asian (SAS) AF: 0.000218 AC: 13 AN: 59614

European-Finnish (FIN) AF: 0.0000809 AC: 1 AN: 12362

Middle Eastern (MID) AF: 0.0140 AC: 16 AN: 1146

European-Non Finnish (NFE) AF: 0.000649 AC: 103 AN: 158630

Other (OTH) AF: 0.00477 AC: 67 AN: 14036

GnomAD4 genome AF: 0.0185 AC: 2820 AN: 152058 Hom.: 74 Cov.: 33 AF XY: 0.0178 AC XY: 1320 AN XY: 74318

African (AFR) AF: 0.0636 AC: 2640 AN: 41512

American (AMR) AF: 0.00577 AC: 88 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000677 AC: 46 AN: 67942

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0119 Hom.: 3

Bravo AF: 0.0218

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis Pigmentosa, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.28
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

Splicing

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

Publications

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Other links and lift over

dbSNP: rs116322351; hg19: chr2-182401996;