2-181536839-C-T

Variant names:

• chr2-181536839-C-T
• rs2368214
• NM_000885.6:c.*1312C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000885.6(ITGA4):​c.*1312C>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 0.997 in 388,496 control chromosomes in the GnomAD database, including 192,962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75085 hom., cov: 32)
  • Exomes 𝑓: 1.0 (117877 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.371
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-181536839-C-T is Benign according to our data. Variant chr2-181536839-C-T is described in ClinVar as Benign. ClinVar VariationId is 332979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.*1312C>T		3_prime_UTR	Exon 28 of 28	NP_000876.3	P13612-1
	CERKL	NM_201548.5	MANE Select	c.*1345G>A		3_prime_UTR	Exon 13 of 13	NP_963842.1	Q49MI3-2
	CERKL	NM_001030311.3		c.*1345G>A		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.*1312C>T		3_prime_UTR	Exon 28 of 28	ENSP00000380227.2	P13612-1
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.*1345G>A		3_prime_UTR	Exon 13 of 13	ENSP00000386725.3	Q49MI3-2
	CERKL	ENST00000684145.1		c.*1345G>A		3_prime_UTR	Exon 12 of 12	ENSP00000508396.1	G0XYE7

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151078 AN: 152126 Hom.: 75035 Cov.: 32

Gnomad AFR AF: 0.977

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.995

GnomAD2 exomes AF: 0.998 AC: 98600 AN: 98794 AF XY: 0.999

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 0.995

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 236000 AN: 236252 Hom.: 117877 Cov.: 0 AF XY: 0.999 AC XY: 132789 AN XY: 132902

African (AFR) AF: 0.982 AC: 6571 AN: 6694

American (AMR) AF: 0.998 AC: 18698 AN: 18734

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 8337 AN: 8376

East Asian (EAS) AF: 1.00 AC: 7917 AN: 7918

South Asian (SAS) AF: 1.00 AC: 45820 AN: 45834

European-Finnish (FIN) AF: 1.00 AC: 10660 AN: 10660

Middle Eastern (MID) AF: 0.998 AC: 890 AN: 892

European-Non Finnish (NFE) AF: 1.00 AC: 125993 AN: 126004

Other (OTH) AF: 0.998 AC: 11114 AN: 11140

GnomAD4 genome AF: 0.993 AC: 151187 AN: 152244 Hom.: 75085 Cov.: 32 AF XY: 0.993 AC XY: 73917 AN XY: 74432

African (AFR) AF: 0.977 AC: 40596 AN: 41554

American (AMR) AF: 0.996 AC: 15205 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3453 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5181 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67993 AN: 68000

Other (OTH) AF: 0.995 AC: 2101 AN: 2112

Alfa AF: 0.997 Hom.: 13973

Bravo AF: 0.992

Asia WGS AF: 0.997 AC: 3467 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.88
DANN	Benign	0.58
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2368214; hg19: chr2-182401566;