2-181536766-A-ACAAT

Variant names:

• chr2-181536766-A-ACAAT
• rs529740971
• NM_000885.6:c.*1242_*1245dupATCA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000885.6(ITGA4):​c.*1242_*1245dupATCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 248,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.85
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 342 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1242_*1245dupATCA		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*1414_*1417dupATTG		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.*1242_*1245dupATCA		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*1414_*1417dupATTG		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*1414_*1417dupATTG		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000890 AC: 23 AN: 25830 AF XY: 0.000585

Gnomad AFR exome AF: 0.00623

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00194

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000342 AC: 33 AN: 96458 Hom.: 0 Cov.: 0 AF XY: 0.000268 AC XY: 14 AN XY: 52220

African (AFR) AF: 0.00709 AC: 15 AN: 2116

American (AMR) AF: 0.000222 AC: 1 AN: 4496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2300

East Asian (EAS) AF: 0.00178 AC: 8 AN: 4506

South Asian (SAS) AF: 0.000175 AC: 3 AN: 17118

European-Finnish (FIN) AF: 0.000199 AC: 1 AN: 5036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 348

European-Non Finnish (NFE) AF: 0.0000539 AC: 3 AN: 55708

Other (OTH) AF: 0.000414 AC: 2 AN: 4830

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74424

African (AFR) AF: 0.00780 AC: 324 AN: 41558

American (AMR) AF: 0.000524 AC: 8 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67964

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00230 Hom.: 1

Bravo AF: 0.00260

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis Pigmentosa, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.9

Splicing

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

Other links and lift over

dbSNP: rs529740971; hg19: chr2-182401493;