19-7745624-C-G

Position:

chr19-7745624-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_021155.4(CD209):c.642G>C(p.Glu214Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 617,376 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0093 ( 2 hom., cov: 30)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

CD209
NM_021155.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 0.0590

Variant links:

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]

CD209 links:

ENSG00000288669 (HGNC:):

ENSG00000288669 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005106002).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00925 (1320/142696) while in subpopulation AFR AF= 0.0361 (1245/34464). AF 95% confidence interval is 0.0345. There are 2 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD209	NM_021155.4 link	c.642G>C	p.Glu214Asp	missense_variant	4/7	ENST00000315599.12	NP_066978.1	Q9NNX6-1B2R907

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD209	ENST00000315599.12 link	c.642G>C	p.Glu214Asp	missense_variant	4/7	1	NM_021155.4	ENSP00000315477.6		Q9NNX6-1
ENSG00000288669	ENST00000678003.1 link	n.39G>C		non_coding_transcript_exon_variant	1/13			ENSP00000504497.1		A0A7I2YQT4

Frequencies

GnomAD3 genomes

AF:

0.00928

AC:

1323

AN:

142608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00372

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000217

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00342

Gnomad NFE

AF:

0.0000895

Gnomad OTH

AF:

0.00605

GnomAD3 exomes

AF:

0.000301

AC:

AN:

232322

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

127668

show subpopulations

Gnomad AFR exome

AF:

0.00559

Gnomad AMR exome

AF:

0.0000590

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000310

AC:

147

AN:

474680

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

AN XY:

255744

show subpopulations

Gnomad4 AFR exome

AF:

0.00915

Gnomad4 AMR exome

AF:

0.000630

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000276

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00925

AC:

1320

AN:

142696

Hom.:

Cov.:

AF XY:

0.00885

AC XY:

615

AN XY:

69528

show subpopulations

Gnomad4 AFR

AF:

0.0361

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000217

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000895

Gnomad4 OTH

AF:

0.00601

Alfa

AF:

0.0267

Hom.:

ExAC

AF:

0.000262

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Mycobacterium tuberculosis, susceptibility to;C1836230:Susceptibility to HIV infection;C3280582:Dengue virus, susceptibility to

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CD209 NM_021155.3 exon 4 p.Glu214Asp (c.642G>C):This variant has not been reported in the literature but is present in 0.5% (59/11200) of African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs11465377). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

CD209-related disorder

Benign:1

Benign, no assertion criteria provided

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

0.28

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.3

DANN

Benign

0.97

DEOGEN2

Benign

0.092

T;.;.;.;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.45

T;T;T;T;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0051

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;.;M;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.55

N;.;N;N;N;.

REVEL

Benign

0.095

Sift

Benign

0.042

D;.;D;D;D;.

Sift4G

Uncertain

0.025

D;D;D;D;D;D

Polyphen

0.046

B;B;B;B;B;B

Vest4

0.27

MutPred

0.065

Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;.;.;

MVP

0.15

MPC

0.052

ClinPred

0.0063

GERP RS

-1.7

Varity_R

0.064

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over