19-7745604-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021155.4(CD209):c.662G>A(p.Arg221Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 617,018 control chromosomes in the GnomAD database, including 7 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 (★).

• Frequency:
  • Genomes: 𝑓 0.013 (5 hom., cov: 30)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: CD209 NM_021155.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.640

Genes affected

CD209 (HGNC:1641): (CD209 molecule) 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 leprosy and tuberculosis mycobacteria, the Ebola, hepatitis C, HIV-1 and Dengue viruses, 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, 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, CLEC4M (Gene ID: 10332), also known as L-SIGN. The two genes differ in viral recognition and expression patterns, with this gene showing high expression on the surface of dendritic cells. Polymorphisms in the neck region are associated with protection from HIV-1 infection, while single nucleotide polymorphisms in the promoter of this gene are associated with differing resistance and susceptibility to and severity of infectious disease, including rs4804803, which is associated with SARS severity. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038184822).
• BP6: Variant 19-7745604-C-T is Benign according to our data. Variant chr19-7745604-C-T is described in ClinVar as [Benign]. Clinvar id is 3038490.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1776/140266) while in subpopulation AFR AF= 0.0485 (1664/34320). AF 95% confidence interval is 0.0465. There are 5 homozygotes in gnomad4. There are 830 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD209	NM_021155.4	c.662G>A	p.Arg221Gln	missense_variant	4/7	ENST00000315599.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD209	ENST00000315599.12	c.662G>A	p.Arg221Gln	missense_variant	4/7	1	NM_021155.4	P2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1778 AN: 140142 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00469

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.000686

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00787

Gnomad NFE AF: 0.000243

Gnomad OTH AF: 0.0112

GnomAD3 exomes AF: 0.000504 AC: 113 AN: 223996 Hom.: 2 AF XY: 0.000259 AC XY: 32 AN XY: 123446

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0000656

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000754

Gnomad OTH exome AF: 0.000553

GnomAD4 exome AF: 0.000390 AC: 186 AN: 476752 Hom.: 2 Cov.: 0 AF XY: 0.000370 AC XY: 95 AN XY: 256682

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.000740

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.0127 AC: 1776 AN: 140266 Hom.: 5 Cov.: 30 AF XY: 0.0121 AC XY: 830 AN XY: 68510

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.00468

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000212

Gnomad4 SAS AF: 0.000686

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000243

Gnomad4 OTH AF: 0.0111

Alfa AF: 0.0170 Hom.: 9

ESP6500AA AF: 0.0963 AC: 369

ESP6500EA AF: 0.00738 AC: 57

ExAC AF: 0.00253 AC: 300

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CD209-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as 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	Benign	0.066
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.081
Dann	Benign	0.22
DEOGEN2	Benign	0.051	T;.;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.000050	N
LIST_S2	Benign	0.40	T;T;T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N;.;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.90	N;.;N;N;N;.
REVEL	Benign	0.020
Sift	Benign	1.0	T;.;T;T;T;.
Sift4G	Benign	0.96	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B
Vest4		0.075
MVP		0.072
MPC		0.062
ClinPred		0.0020	T
GERP RS		-1.1
Varity_R		0.015
gMVP		0.062

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: rs41335247; hg19: chr19-7810490; COSMIC: COSV52655825;