2-181536661-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000885.6(ITGA4):c.*1134C>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 0.0204 in 179,880 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (142 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-181536661-C-T is Benign according to our data. Variant chr2-181536661-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369320.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA4	NM_000885.6	c.*1134C>T		3_prime_UTR_variant	28/28	ENST00000397033.7
CERKL	NM_201548.5			downstream_gene_variant		ENST00000410087.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7	c.*1134C>T		3_prime_UTR_variant	28/28	1	NM_000885.6	P1
CERKL	ENST00000684145.1	c.*1523G>A		3_prime_UTR_variant	12/12
CERKL	ENST00000410087.8			downstream_gene_variant		1	NM_201548.5	P1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3604 AN: 151494 Hom.: 143 Cov.: 33

Gnomad AFR AF: 0.0822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00829

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.0173

GnomAD3 exomes AF: 0.00394 AC: 30 AN: 7622 Hom.: 2 AF XY: 0.00302 AC XY: 12 AN XY: 3976

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.00750

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00220

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.00485

GnomAD4 exome AF: 0.00191 AC: 54 AN: 28268 Hom.: 3 Cov.: 0 AF XY: 0.00160 AC XY: 24 AN XY: 14974

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00654

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00191

Gnomad4 SAS exome AF: 0.000862

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.0239 AC: 3618 AN: 151612 Hom.: 142 Cov.: 33 AF XY: 0.0230 AC XY: 1708 AN XY: 74128

Gnomad4 AFR AF: 0.0823

Gnomad4 AMR AF: 0.00828

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.000834

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.00740 Hom.: 11

Bravo AF: 0.0271

Asia WGS AF: 0.00925 AC: 32 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	6.5
Dann	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2368213; hg19: chr2-182401388;