2-181536860-C-T

Variant names:

• chr2-181536860-C-T
• rs11553355
• NM_000885.6:c.*1333C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000885.6(ITGA4):​c.*1333C>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 0.0178 in 427,446 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 33)
  • Exomes 𝑓: 0.018 (65 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.433
• Publications: 0 publications found

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]

CERKL Gene-Disease associations (from GenCC):

• CERKL-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 26

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0168 (2556/152008) while in subpopulation NFE AF = 0.0276 (1874/67944). AF 95% confidence interval is 0.0265. There are 33 homozygotes in GnomAd4. There are 1152 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2556 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1333C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*1324G>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.*1333C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*1324G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*1324G>A		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2558 AN: 151888 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00484

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0153 AC: 1764 AN: 114956 AF XY: 0.0153

Gnomad AFR exome AF: 0.00402

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.00643

Gnomad EAS exome AF: 0.000102

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0183 AC: 5033 AN: 275438 Hom.: 65 Cov.: 0 AF XY: 0.0168 AC XY: 2626 AN XY: 156534

African (AFR) AF: 0.00548 AC: 43 AN: 7852

American (AMR) AF: 0.0155 AC: 370 AN: 23900

Ashkenazi Jewish (ASJ) AF: 0.00728 AC: 72 AN: 9894

East Asian (EAS) AF: 0.000115 AC: 1 AN: 8674

South Asian (SAS) AF: 0.00245 AC: 131 AN: 53388

European-Finnish (FIN) AF: 0.0133 AC: 156 AN: 11686

Middle Eastern (MID) AF: 0.0186 AC: 19 AN: 1020

European-Non Finnish (NFE) AF: 0.0275 AC: 4015 AN: 146140

Other (OTH) AF: 0.0175 AC: 226 AN: 12884

GnomAD4 genome AF: 0.0168 AC: 2556 AN: 152008 Hom.: 33 Cov.: 33 AF XY: 0.0155 AC XY: 1152 AN XY: 74296

African (AFR) AF: 0.00482 AC: 200 AN: 41478

American (AMR) AF: 0.0180 AC: 275 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10564

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0276 AC: 1874 AN: 67944

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.0209 Hom.: 6

Bravo AF: 0.0168

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.48
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs11553355; hg19: chr2-182401587;