2-181536661-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000885.6(ITGA4):c.*1134C>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 0.0204 in 179,880 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.024 ( 142 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

ITGA4
NM_000885.6 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00

Publications

1 publications found

Variant links:

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]

ITGA4 links:

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

CERKL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 2-181536661-C-T is Benign according to our data. Variant chr2-181536661-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369320.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6 link	c.*1134C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3	P13612-1
CERKL	NM_201548.5 link	c.*1523G>A		downstream_gene_variant		ENST00000410087.8	NP_963842.1	Q49MI3-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGA4	ENST00000397033.7 link	c.*1134C>T	3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2	P13612-1
CERKL	ENST00000684145.1 link	c.*1523G>A	3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1	G0XYE7
CERKL	ENST00000410087.8 link	c.*1523G>A	downstream_gene_variant		1	NM_201548.5	ENSP00000386725.3	Q49MI3-2

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3604

AN:

151494

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0822

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00829

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.000833

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.00394

AC:

AN:

7622

AF XY:

0.00302

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.00750

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00220

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000277

Gnomad OTH exome

AF:

0.00485

GnomAD4 exome

AF:

0.00191

AC:

AN:

28268

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

AN XY:

14974

show subpopulations

African (AFR)

AF:

0.117

AC:

AN:

240

American (AMR)

AF:

0.00654

AC:

AN:

2140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

550

East Asian (EAS)

AF:

0.00191

AC:

AN:

1048

South Asian (SAS)

AF:

0.000862

AC:

AN:

4642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000122

AC:

AN:

16408

Other (OTH)

AF:

0.00262

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0239

AC:

3618

AN:

151612

Hom.:

142

Cov.:

AF XY:

0.0230

AC XY:

1708

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.0823

AC:

3408

AN:

41396

American (AMR)

AF:

0.00828

AC:

126

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00483

AC:

AN:

5176

South Asian (SAS)

AF:

0.000834

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000280

AC:

AN:

67762

Other (OTH)

AF:

0.0171

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

173

346

519

692

865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.0271

Asia WGS

AF:

0.00925

AC:

AN:

3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinitis Pigmentosa, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.5

(source)

DANN

Benign

0.62

PhyloP100

0.0

Splicing

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

Publications

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2-181536661-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over