2-181537489-C-CT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000885.6(ITGA4):c.*1968dup variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 453,530 control chromosomes in the GnomAD database, including 174 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (41 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.838

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 -10 ACMG points.

• BP6: Variant 2-181537489-C-CT is Benign according to our data. Variant chr2-181537489-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 332991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA4	NM_000885.6	c.*1968dup		3_prime_UTR_variant	28/28	ENST00000397033.7
CERKL	NM_201548.5	c.*694_*695insA		3_prime_UTR_variant	13/13	ENST00000410087.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7	c.*1968dup		3_prime_UTR_variant	28/28	1	NM_000885.6	P1
CERKL	ENST00000410087.8	c.*694_*695insA		3_prime_UTR_variant	13/13	1	NM_201548.5	P1
CERKL	ENST00000409440.7	c.*694_*695insA		3_prime_UTR_variant	13/13	2
CERKL	ENST00000684145.1	c.*694_*695insA		3_prime_UTR_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3716 AN: 151946 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00866

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.0221

GnomAD3 exomes AF: 0.00625 AC: 798 AN: 127620 Hom.: 32 AF XY: 0.00525 AC XY: 367 AN XY: 69908

Gnomad AFR exome AF: 0.0933

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.00472

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000269

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000975

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00393 AC: 1185 AN: 301468 Hom.: 41 Cov.: 0 AF XY: 0.00320 AC XY: 550 AN XY: 171804

Gnomad4 AFR exome AF: 0.0874

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000252

Gnomad4 FIN exome AF: 0.0000810

Gnomad4 NFE exome AF: 0.000725

Gnomad4 OTH exome AF: 0.00670

GnomAD4 genome AF: 0.0245 AC: 3721 AN: 152062 Hom.: 133 Cov.: 32 AF XY: 0.0235 AC XY: 1744 AN XY: 74342

Gnomad4 AFR AF: 0.0836

Gnomad4 AMR AF: 0.00865

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.0219

Alfa AF: 0.0117 Hom.: 8

Bravo AF: 0.0285

Asia WGS AF: 0.00433 AC: 15 AN: 3476

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs140597682; hg19: chr2-182402216;