chr12-8515301-A-G

Position:

• chr12-8515301-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000299665.3(CLEC4D):​c.94A>G​(p.Ser32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,467,864 control chromosomes in the GnomAD database, including 45,687 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (9433 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36254 hom.)
• Consequence: CLEC4D ENST00000299665.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.165

Genes affected

CLEC4D (HGNC:14554): (C-type lectin domain family 4 member D) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.259169E-5).
• BP6: Variant 12-8515301-A-G is Benign according to our data. Variant chr12-8515301-A-G is described in ClinVar as [Benign]. Clinvar id is 402542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC4D	NM_080387.5	c.94A>G	p.Ser32Gly	missense_variant	2/6	ENST00000299665.3	NP_525126.2
CLEC4D	XM_011520632.3	c.94A>G	p.Ser32Gly	missense_variant	3/7		XP_011518934.1
CLEC4D	XM_047428771.1	c.94A>G	p.Ser32Gly	missense_variant	2/6		XP_047284727.1
CLEC4D	XM_047428772.1	c.94A>G	p.Ser32Gly	missense_variant	2/6		XP_047284728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC4D	ENST00000299665.3	c.94A>G	p.Ser32Gly	missense_variant	2/6	1	NM_080387.5	ENSP00000299665.2
CLEC4D	ENST00000382064.6	c.94A>G	p.Ser32Gly	missense_variant	3/6	3		ENSP00000371496.2

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47826 AN: 151746 Hom.: 9414 Cov.: 31

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.330

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.234 AC: 58438 AN: 249968 Hom.: 8324 AF XY: 0.233 AC XY: 31450 AN XY: 135144

Gnomad AFR exome AF: 0.565

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.230

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.222 AC: 292122 AN: 1316000 Hom.: 36254 Cov.: 23 AF XY: 0.222 AC XY: 147034 AN XY: 662298

Gnomad4 AFR exome AF: 0.577

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.315 AC: 47903 AN: 151864 Hom.: 9433 Cov.: 31 AF XY: 0.313 AC XY: 23227 AN XY: 74238

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.314

Alfa AF: 0.244 Hom.: 10933

Bravo AF: 0.327

TwinsUK AF: 0.214 AC: 793

ALSPAC AF: 0.217 AC: 835

ESP6500AA AF: 0.549 AC: 2420

ESP6500EA AF: 0.231 AC: 1987

ExAC AF: 0.246 AC: 29918

Asia WGS AF: 0.209 AC: 726 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.242

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.14
DANN	Benign	0.56
DEOGEN2	Benign	0.067	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.000023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.019
Sift	Benign	0.19	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0030	.;B
Vest4		0.17
MPC		0.029
ClinPred		0.0041	T
GERP RS		-0.30
Varity_R		0.052
gMVP		0.23

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: rs4304840; hg19: chr12-8667897; COSMIC: COSV55230143; COSMIC: COSV55230143;