2-181537304-C-T

Variant names:

• chr2-181537304-C-T
• rs1037623
• NM_000885.6:c.*1777C>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.*1777C>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 0.997 in 453,948 control chromosomes in the GnomAD database, including 225,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75033 hom., cov: 31)
  • Exomes 𝑓: 1.0 (150500 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.33

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=-1.0).
• BP6: Variant 2-181537304-C-T is Benign according to our data. Variant chr2-181537304-C-T is described in ClinVar as [Benign]. Clinvar id is 332987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1777C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*880G>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.*1777C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*880G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*880G>A		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1
CERKL	ENST00000409440.7	c.*880G>A		downstream_gene_variant		2		ENSP00000387080.3

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151002 AN: 152072 Hom.: 74983 Cov.: 31

Gnomad AFR AF: 0.977

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.996

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.998 AC: 127662 AN: 127950 AF XY: 0.998

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 0.995

Gnomad EAS exome AF: 0.994

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 301376 AN: 301758 Hom.: 150500 Cov.: 0 AF XY: 0.999 AC XY: 171806 AN XY: 171972

African (AFR) AF: 0.981 AC: 8384 AN: 8548

American (AMR) AF: 0.998 AC: 27231 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 10738 AN: 10786

East Asian (EAS) AF: 0.995 AC: 9161 AN: 9208

South Asian (SAS) AF: 1.00 AC: 59619 AN: 59642

European-Finnish (FIN) AF: 1.00 AC: 12364 AN: 12364

Middle Eastern (MID) AF: 0.998 AC: 1148 AN: 1150

European-Non Finnish (NFE) AF: 1.00 AC: 158718 AN: 158744

Other (OTH) AF: 0.998 AC: 14013 AN: 14042

GnomAD4 genome AF: 0.993 AC: 151111 AN: 152190 Hom.: 75033 Cov.: 31 AF XY: 0.993 AC XY: 73889 AN XY: 74418

African (AFR) AF: 0.977 AC: 40566 AN: 41520

American (AMR) AF: 0.996 AC: 15201 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3455 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5151 AN: 5174

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67993 AN: 68002

Other (OTH) AF: 0.994 AC: 2099 AN: 2112

Alfa AF: 0.996 Hom.: 13988

Bravo AF: 0.992

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	-1.0
CADD	Benign	0.16
DANN	Benign	0.53
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1037623; hg19: chr2-182402031;