19-7745624-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E214G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0093 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: CD209 NM_021155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0590

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005106002).
• BP6: Variant 19-7745624-C-G is Benign according to our data. Variant chr19-7745624-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 625909.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• 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.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD209	NM_021155.4	c.642G>C	p.Glu214Asp	missense_variant	4/7	ENST00000315599.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD209	ENST00000315599.12	c.642G>C	p.Glu214Asp	missense_variant	4/7	1	NM_021155.4	P2

Frequencies

GnomAD3 genomes AF: 0.00928 AC: 1323 AN: 142608 Hom.: 2 Cov.: 30

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: 70 AN: 232322 Hom.: 1 AF XY: 0.000141 AC XY: 18 AN XY: 127668

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.: 1 Cov.: 0 AF XY: 0.000278 AC XY: 71 AN XY: 255744

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.: 2 Cov.: 30 AF XY: 0.00885 AC XY: 615 AN XY: 69528

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.: 0

ExAC AF: 0.000262 AC: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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, 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	0.28
BayesDel_addAF	Benign	-0.59	T
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	N
LIST_S2	Benign	0.45	T;T;T;T;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0051	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs11465377; hg19: chr19-7810510; COSMIC: COSV99041244;