2-181537269-G-C

Position:

• chr2-181537269-G-C

Variant summary

Our verdict is Benign. Variant got -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]

CERKL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1742G>C		3_prime_UTR_variant	28/28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*915C>G		3_prime_UTR_variant	13/13	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.*1742G>C		3_prime_UTR_variant	28/28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087	c.*915C>G		3_prime_UTR_variant	13/13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145	c.*915C>G		3_prime_UTR_variant	12/12			ENSP00000508396.1

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

GnomAD3 exomes AF: 0.00447 AC: 572 AN: 127846 Hom.: 18 AF XY: 0.00384 AC XY: 269 AN XY: 70028

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 SAS exome AF: 0.000223

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

Gnomad4 AFR exome AF: 0.0654

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00213

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000218

Gnomad4 FIN exome AF: 0.0000809

Gnomad4 NFE exome AF: 0.000649

Gnomad4 OTH exome AF: 0.00477

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

Gnomad4 AFR AF: 0.0636

Gnomad4 AMR AF: 0.00577

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000677

Gnomad4 OTH AF: 0.0156

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.28

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs116322351; hg19: chr2-182401996;