rs188892870

Variant names:

• chr2-181537611-T-C
• rs188892870
• NM_000885.6:c.*2084T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000885.6(ITGA4):​c.*2084T>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 0.00121 in 430,540 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.676
• 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: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS2: High AC in GnomAd4 at 422 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000885.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	NM_000885.6	MANE Select	c.*2084T>C		3_prime_UTR	Exon 28 of 28	NP_000876.3	P13612-1
	CERKL	NM_201548.5	MANE Select	c.*573A>G		3_prime_UTR	Exon 13 of 13	NP_963842.1	Q49MI3-2
	CERKL	NM_001030311.3		c.*573A>G		3_prime_UTR	Exon 14 of 14	NP_001025482.1	Q49MI3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.*2084T>C		3_prime_UTR	Exon 28 of 28	ENSP00000380227.2	P13612-1
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.*573A>G		3_prime_UTR	Exon 13 of 13	ENSP00000386725.3	Q49MI3-2
	CERKL	ENST00000409440.7	TSL:2	c.*573A>G		3_prime_UTR	Exon 13 of 13	ENSP00000387080.3	Q49MI3-9

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 422 AN: 152058 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00954

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000712 AC: 76 AN: 106804 AF XY: 0.000410

Gnomad AFR exome AF: 0.00911

Gnomad AMR exome AF: 0.000991

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000484

Gnomad OTH exome AF: 0.000904

GnomAD4 exome AF: 0.000348 AC: 97 AN: 278364 Hom.: 1 Cov.: 0 AF XY: 0.000208 AC XY: 33 AN XY: 158888

African (AFR) AF: 0.00988 AC: 70 AN: 7084

American (AMR) AF: 0.000925 AC: 20 AN: 21620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9646

East Asian (EAS) AF: 0.00 AC: 0 AN: 9072

South Asian (SAS) AF: 0.00 AC: 0 AN: 54304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 998

European-Non Finnish (NFE) AF: 0.00000662 AC: 1 AN: 151070

Other (OTH) AF: 0.000462 AC: 6 AN: 12974

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152176 Hom.: 3 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74418

African (AFR) AF: 0.00951 AC: 395 AN: 41526

American (AMR) AF: 0.00118 AC: 18 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.00322

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.4
DANN	Benign	0.87
PhyloP100		0.68
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: rs188892870; hg19: chr2-182402338;