19-7745700-T-A

Position:

• chr19-7745700-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021155.4(CD209):​c.566A>T​(p.Gln189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,567,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: CD209 NM_021155.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.95

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06732795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD209	NM_021155.4	c.566A>T	p.Gln189Leu	missense_variant	4/7	ENST00000315599.12	NP_066978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD209	ENST00000315599.12	c.566A>T	p.Gln189Leu	missense_variant	4/7	1	NM_021155.4	ENSP00000315477.6
ENSG00000288669	ENST00000678003.1	n.-38A>T		upstream_gene_variant				ENSP00000504497.1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 85 AN: 121966 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000251

Gnomad ASJ AF: 0.000673

Gnomad EAS AF: 0.000746

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000648

Gnomad MID AF: 0.0106

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.000620

GnomAD4 exome AF: 0.0000533 AC: 77 AN: 1445822 Hom.: 0 Cov.: 33 AF XY: 0.0000486 AC XY: 35 AN XY: 719606

Gnomad4 AFR exome AF: 0.000814

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000269

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000705 AC: 86 AN: 122022 Hom.: 0 Cov.: 26 AF XY: 0.000620 AC XY: 37 AN XY: 59686

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000251

Gnomad4 ASJ AF: 0.000673

Gnomad4 EAS AF: 0.000747

Gnomad4 SAS AF: 0.000264

Gnomad4 FIN AF: 0.000648

Gnomad4 NFE AF: 0.000386

Gnomad4 OTH AF: 0.000613

Alfa AF: 0.0167 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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.Gln189Leu (c.566A>T): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.8
DANN	Benign	0.82
DEOGEN2	Benign	0.049	T;T;.;.;.;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.48	T;T;T;T;T;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.067	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;.;L;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.55	N;.;.;N;N;N;.
REVEL	Benign	0.091
Sift	Benign	1.0	T;.;.;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;.;P;B;B;P;B
Vest4		0.35
MutPred		0.19		Loss of methylation at K186 (P = 0.1375);.;.;Loss of methylation at K186 (P = 0.1375);.;.;.;
MVP		0.16
MPC		0.054
ClinPred		0.019	T
GERP RS		1.0
Varity_R		0.048
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: rs749759932; hg19: chr19-7810586; COSMIC: COSV52649820; COSMIC: COSV52649820;