2-181537489-C-CT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_000885.6(ITGA4):c.*1968dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 453,530 control chromosomes in the GnomAD database, including 174 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.024 ( 133 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 41 hom. )

Consequence

ITGA4
NM_000885.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.838

Publications

0 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 -10 ACMG points.

BP6

Variant 2-181537489-C-CT is Benign according to our data. Variant chr2-181537489-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 332991.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6 link	c.*1968dupT		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3	P13612-1
CERKL	NM_201548.5 link	c.*694dupA		3_prime_UTR_variant	Exon 13 of 13	ENST00000410087.8	NP_963842.1	Q49MI3-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGA4	ENST00000397033.7 link	c.*1968dupT	3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2	P13612-1
CERKL	ENST00000410087.8 link	c.*694dupA	3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3	Q49MI3-2
CERKL	ENST00000409440.7 link	c.*694dupA	3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000387080.3	Q49MI3-9
CERKL	ENST00000684145.1 link	c.*694dupA	3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1	G0XYE7

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3716

AN:

151946

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0837

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00866

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000780

Gnomad OTH

AF:

0.0221

GnomAD2 exomes

AF:

0.00625

AC:

798

AN:

127620

AF XY:

0.00525

show subpopulations

Gnomad AFR exome

AF:

0.0933

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.00472

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000188

Gnomad NFE exome

AF:

0.000975

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00393

AC:

1185

AN:

301468

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

550

AN XY:

171804

show subpopulations

African (AFR)

AF:

0.0874

AC:

746

AN:

8536

American (AMR)

AF:

0.00521

AC:

142

AN:

27254

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

AN:

10762

East Asian (EAS)

AF:

0.00

AC:

AN:

9204

South Asian (SAS)

AF:

0.000252

AC:

AN:

59620

European-Finnish (FIN)

AF:

0.0000810

AC:

AN:

12342

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

1146

European-Non Finnish (NFE)

AF:

0.000725

AC:

115

AN:

158582

Other (OTH)

AF:

0.00670

AC:

AN:

14022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0245

AC:

3721

AN:

152062

Hom.:

133

Cov.:

AF XY:

0.0235

AC XY:

1744

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0836

AC:

3465

AN:

41472

American (AMR)

AF:

0.00865

AC:

132

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000780

AC:

AN:

67954

Other (OTH)

AF:

0.0219

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

177

353

530

706

883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.0285

Asia WGS

AF:

0.00433

AC:

AN:

3476

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

PhyloP100

0.84

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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2-181537489-C-CT

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