19-7745673-C-T

Variant names:

• chr19-7745673-C-T
• rs41374747
• NM_021155.4:c.593G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021155.4(CD209):​c.593G>A​(p.Arg198Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 136,262 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 27)
  • Exomes 𝑓: 0.000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD209 NM_021155.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.341
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013873458).
• BP6: Variant 19-7745673-C-T is Benign according to our data. Variant chr19-7745673-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021155.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD209	NM_021155.4	MANE Select	c.593G>A	p.Arg198Gln	missense	Exon 4 of 7	NP_066978.1	Q9NNX6-1
	CD209	NM_001144897.2		c.593G>A	p.Arg198Gln	missense	Exon 4 of 7	NP_001138369.1	Q9NNX6-2
	CD209	NM_001144896.2		c.521G>A	p.Arg174Gln	missense	Exon 3 of 6	NP_001138368.1	Q9NNX6-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD209	ENST00000315599.12	TSL:1 MANE Select	c.593G>A	p.Arg198Gln	missense	Exon 4 of 7	ENSP00000315477.6	Q9NNX6-1
	CD209	ENST00000354397.10	TSL:1	c.593G>A	p.Arg198Gln	missense	Exon 4 of 7	ENSP00000346373.5	Q9NNX6-2
	CD209	ENST00000315591.12	TSL:1	c.521G>A	p.Arg174Gln	missense	Exon 3 of 6	ENSP00000315407.7	Q9NNX6-6

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 341 AN: 136178 Hom.: 2 Cov.: 27

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000494

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000307

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.0000513 AC: 12 AN: 234060 AF XY: 0.0000623

Gnomad AFR exome AF: 0.000921

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000147 AC: 7 AN: 475178 Hom.: 0 Cov.: 0 AF XY: 0.0000195 AC XY: 5 AN XY: 256084

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000191 AC: 2 AN: 10498

American (AMR) AF: 0.0000519 AC: 1 AN: 19280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13966

East Asian (EAS) AF: 0.00 AC: 0 AN: 31924

South Asian (SAS) AF: 0.00 AC: 0 AN: 47146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2062

European-Non Finnish (NFE) AF: 0.00000689 AC: 2 AN: 290410

Other (OTH) AF: 0.0000744 AC: 2 AN: 26866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000291982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00251 AC: 342 AN: 136262 Hom.: 2 Cov.: 27 AF XY: 0.00262 AC XY: 174 AN XY: 66480

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0102 AC: 327 AN: 32016

American (AMR) AF: 0.000494 AC: 7 AN: 14184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4752

South Asian (SAS) AF: 0.000233 AC: 1 AN: 4292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.0000307 AC: 2 AN: 65168

Other (OTH) AF: 0.00263 AC: 5 AN: 1898

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000516 Hom.: 0

ExAC AF: 0.00000844 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.011
DANN	Benign	0.26
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00035	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-0.34
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.012	B
Vest4		0.13
MVP		0.072
MPC		0.062
ClinPred		0.0086	T
GERP RS		-2.1
Varity_R		0.015
gMVP		0.033
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs41374747; hg19: chr19-7810559; COSMIC: COSV52656716;