19-7745631-T-A

Position:

• chr19-7745631-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.635A>T​(p.Gln212Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000934 in 115,654 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 0.00093 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD209 NM_021155.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.168

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]

ENSG00000288669 (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=0.045265913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD209	NM_021155.4	c.635A>T	p.Gln212Leu	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.635A>T	p.Gln212Leu	missense_variant	4/7	1	NM_021155.4	ENSP00000315477.6
ENSG00000288669	ENST00000678003.1	n.32A>T		non_coding_transcript_exon_variant	1/13			ENSP00000504497.1

Frequencies

GnomAD3 genomes AF: 0.000908 AC: 105 AN: 115598 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000710

Gnomad AMI AF: 0.00296

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.000693

Gnomad EAS AF: 0.00159

Gnomad SAS AF: 0.000571

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000307

Gnomad OTH AF: 0.000646

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000128 AC: 6 AN: 470530 Hom.: 0 Cov.: 0 AF XY: 0.0000158 AC XY: 4 AN XY: 253326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000315

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000701

Gnomad4 OTH exome AF: 0.0000375

GnomAD4 genome AF: 0.000934 AC: 108 AN: 115654 Hom.: 0 Cov.: 27 AF XY: 0.000897 AC XY: 50 AN XY: 55760

Gnomad4 AFR AF: 0.000742

Gnomad4 AMR AF: 0.000875

Gnomad4 ASJ AF: 0.000693

Gnomad4 EAS AF: 0.00159

Gnomad4 SAS AF: 0.000859

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.000307

Gnomad4 OTH AF: 0.000642

Alfa AF: 0.00705 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.635A>T (p.Q212L) alteration is located in exon 4 (coding exon 4) of the CD209 gene. This alteration results from a A to T substitution at nucleotide position 635, causing the glutamine (Q) at amino acid position 212 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.40
DANN	Benign	0.17
DEOGEN2	Benign	0.050	T;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.56	T;T;T;T;T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.045	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.090	N;.;N;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.26	N;.;N;N;N;.
REVEL	Benign	0.027
Sift	Benign	0.67	T;.;T;T;T;.
Sift4G	Benign	0.48	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.32
MutPred		0.18		Loss of ubiquitination at K209 (P = 0.0666);.;Loss of ubiquitination at K209 (P = 0.0666);.;.;.;
MVP		0.048
MPC		0.054
ClinPred		0.017	T
GERP RS		-0.10
Varity_R		0.037
gMVP		0.28

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: rs1416643961; hg19: chr19-7810517; COSMIC: COSV52649850;