3-111545361-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_005816.5(CD96):c.377G>A(p.Gly126Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CD96 NM_005816.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.52

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• BP6: Variant 3-111545361-G-A is Benign according to our data. Variant chr3-111545361-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3060763.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD96	NM_005816.5	c.377G>A	p.Gly126Asp	missense_variant	2/14	ENST00000352690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD96	ENST00000352690.9	c.377G>A	p.Gly126Asp	missense_variant	2/14	1	NM_005816.5	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000483 AC: 12 AN: 248674 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460948 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.377G>A (p.G126D) alteration is located in exon 2 (coding exon 2) of the CD96 gene. This alteration results from a G to A substitution at nucleotide position 377, causing the glycine (G) at amino acid position 126 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CD96-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	0.75	D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.070	T;T;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.67		Loss of ubiquitination at K130 (P = 0.0801);Loss of ubiquitination at K130 (P = 0.0801);Loss of ubiquitination at K130 (P = 0.0801);
MVP		0.65
MPC		0.16
ClinPred		0.48	T
GERP RS		4.3
Varity_R		0.55
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1170323393; hg19: chr3-111264208; COSMIC: COSV105106755; COSMIC: COSV105106755;