rs2277998

Variant names:

• chr19-7766742-G-A
• rs2277998
• NM_014257.5:c.871G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014257.5(CLEC4M):​c.871G>A​(p.Asp291Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,614,058 control chromosomes in the GnomAD database, including 67,733 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (5214 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62519 hom.)
• Consequence: CLEC4M NM_014257.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• Publications: 36 publications found

Genes affected

CLEC4M (HGNC:13523): (C-type lectin domain family 4 member M) This gene encodes a C-type lectin that functions in cell adhesion and pathogen recognition. This receptor recognizes a wide range of evolutionarily divergent pathogens with a large impact on public health, including tuberculosis mycobacteria, and viruses including Ebola, hepatitis C, HIV-1, influenza A, West Nile virus and the SARS-CoV acute respiratory syndrome coronavirus. The protein is organized into four distinct domains: a C-terminal carbohydrate recognition domain, a flexible tandem-repeat neck domain of variable length, a transmembrane region and an N-terminal cytoplasmic domain involved in internalization. This gene is closely related in terms of both sequence and function to a neighboring gene, CD209 (Gene ID: 30835), also known as DC-SIGN. The two genes differ in viral recognition and expression patterns, with this gene showing high expression in endothelial cells of the liver, lymph node and placenta. Polymorphisms in the tandem repeat neck domain are associated with resistance to SARS infection. [provided by RefSeq, May 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009361863).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC4M	NM_014257.5	c.871G>A	p.Asp291Asn	missense_variant	Exon 5 of 7	ENST00000327325.10	NP_055072.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC4M	ENST00000327325.10	c.871G>A	p.Asp291Asn	missense_variant	Exon 5 of 7	1	NM_014257.5	ENSP00000316228.4

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35648 AN: 152080 Hom.: 5205 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.269 AC: 67727 AN: 251452 AF XY: 0.271

Gnomad AFR exome AF: 0.0543

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.288 AC: 421035 AN: 1461860 Hom.: 62519 Cov.: 63 AF XY: 0.287 AC XY: 209058 AN XY: 727238

African (AFR) AF: 0.0480 AC: 1607 AN: 33480

American (AMR) AF: 0.327 AC: 14611 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5213 AN: 26136

East Asian (EAS) AF: 0.156 AC: 6207 AN: 39696

South Asian (SAS) AF: 0.212 AC: 18290 AN: 86256

European-Finnish (FIN) AF: 0.299 AC: 15969 AN: 53418

Middle Eastern (MID) AF: 0.242 AC: 1393 AN: 5768

European-Non Finnish (NFE) AF: 0.307 AC: 341793 AN: 1111992

Other (OTH) AF: 0.264 AC: 15952 AN: 60394

GnomAD4 genome AF: 0.234 AC: 35662 AN: 152198 Hom.: 5214 Cov.: 32 AF XY: 0.234 AC XY: 17440 AN XY: 74398

African (AFR) AF: 0.0632 AC: 2626 AN: 41542

American (AMR) AF: 0.327 AC: 4995 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3472

East Asian (EAS) AF: 0.153 AC: 791 AN: 5172

South Asian (SAS) AF: 0.205 AC: 992 AN: 4832

European-Finnish (FIN) AF: 0.308 AC: 3253 AN: 10578

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21180 AN: 68010

Other (OTH) AF: 0.250 AC: 528 AN: 2112

Alfa AF: 0.274 Hom.: 11639

Bravo AF: 0.230

TwinsUK AF: 0.310 AC: 1151

ALSPAC AF: 0.291 AC: 1122

ESP6500AA AF: 0.0685 AC: 302

ESP6500EA AF: 0.314 AC: 2704

ExAC AF: 0.265 AC: 32184

Asia WGS AF: 0.173 AC: 603 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.323

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0080
DANN	Benign	0.71
DEOGEN2	Benign	0.031	.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0094	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.
PhyloP100		-2.3
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.7	D;.;D;D;D;.;.;.;.;.
REVEL	Benign	0.023
Sift	Benign	0.19	T;.;T;T;T;.;.;.;.;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030, 0.0090, 0.029, 0.10, 0.0060, 0.010, 0.075	.;B;B;B;B;B;.;.;B;B
Vest4		0.090
MPC		0.24
ClinPred		0.0064	T
GERP RS		-5.1
Varity_R		0.12
gMVP		0.24
Mutation Taster		=94/6	polymorphism (auto)

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: rs2277998; hg19: chr19-7831628; COSMIC: COSV50219193;