rs200703204

Variant names:

• chr3-111542298-A-AT
• rs200703204
• NM_005816.5:c.54dupT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_198196.3(CD96):​c.54dupT​(p.Val19CysfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,613,716 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: CD96 NM_198196.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.426
• Publications: 3 publications found

Genes affected

CD96 (HGNC:16892): (CD96 molecule) The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

CD96 Gene-Disease associations (from GenCC):

• C syndrome

  Inheritance: Unknown, AD, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.969 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• BP6: Variant 3-111542298-A-AT is Benign according to our data. Variant chr3-111542298-A-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225311.
• BS2: High Homozygotes in GnomAdExome4 at 2 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198196.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD96	NM_005816.5	MANE Select	c.54dupT	p.Val19CysfsTer22	frameshift	Exon 1 of 14	NP_005807.1
	CD96	NM_198196.3		c.54dupT	p.Val19CysfsTer22	frameshift	Exon 1 of 15	NP_937839.1
	CD96	NM_001410800.1		c.54dupT	p.Val19CysfsTer22	frameshift	Exon 1 of 14	NP_001397729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD96	ENST00000352690.9	TSL:1 MANE Select	c.54dupT	p.Val19CysfsTer22	frameshift	Exon 1 of 14	ENSP00000342040.3
	CD96	ENST00000283285.10	TSL:1	c.54dupT	p.Val19CysfsTer22	frameshift	Exon 1 of 15	ENSP00000283285.5
	CD96	ENST00000438817.6	TSL:1	c.54dupT	p.Val19CysfsTer22	frameshift	Exon 1 of 8	ENSP00000389801.2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152080 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000713 AC: 179 AN: 250926 AF XY: 0.000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00565

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1461518 Hom.: 2 Cov.: 31 AF XY: 0.000215 AC XY: 156 AN XY: 727070

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00132 AC: 59 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26132

East Asian (EAS) AF: 0.00516 AC: 205 AN: 39694

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111674

Other (OTH) AF: 0.000182 AC: 11 AN: 60388

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152198 Hom.: 1 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74398

African (AFR) AF: 0.0000482 AC: 2 AN: 41534

American (AMR) AF: 0.000654 AC: 10 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00696 AC: 36 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000404

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	C syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=39/161	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200703204; hg19: chr3-111261145;