NM_021155.4:c.731A>G

Variant names:

• chr19-7745535-T-C
• rs145850292
• NM_021155.4:c.731A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_021155.4(CD209):​c.731A>G​(p.Gln244Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 144,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q244E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD209 NM_021155.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.782
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026685715).
• BP6: Variant 19-7745535-T-C is Benign according to our data. Variant chr19-7745535-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2649173.Status of the report is criteria_provided_single_submitter, 1 stars.

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.731A>G	p.Gln244Arg	missense	Exon 4 of 7	NP_066978.1	Q9NNX6-1
	CD209	NM_001144897.2		c.731A>G	p.Gln244Arg	missense	Exon 4 of 7	NP_001138369.1	Q9NNX6-2
	CD209	NM_001144896.2		c.659A>G	p.Gln220Arg	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.731A>G	p.Gln244Arg	missense	Exon 4 of 7	ENSP00000315477.6	Q9NNX6-1
	CD209	ENST00000354397.10	TSL:1	c.731A>G	p.Gln244Arg	missense	Exon 4 of 7	ENSP00000346373.5	Q9NNX6-2
	CD209	ENST00000315591.12	TSL:1	c.659A>G	p.Gln220Arg	missense	Exon 3 of 6	ENSP00000315407.7	Q9NNX6-6

Frequencies

GnomAD3 genomes AF: 0.000298 AC: 43 AN: 144448 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000692

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000208

Gnomad SAS AF: 0.000442

Gnomad FIN AF: 0.000312

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000122

Gnomad OTH AF: 0.000998

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250828 AF XY: 0.00

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

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: 0.00000480 AC: 7 AN: 1458242 Hom.: 0 Cov.: 35 AF XY: 0.00000414 AC XY: 3 AN XY: 725444

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

African (AFR) AF: 0.0000903 AC: 3 AN: 33240

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4526

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110706

Other (OTH) AF: 0.0000166 AC: 1 AN: 60126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000297 AC: 43 AN: 144556 Hom.: 0 Cov.: 31 AF XY: 0.000283 AC XY: 20 AN XY: 70616

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

African (AFR) AF: 0.000690 AC: 27 AN: 39108

American (AMR) AF: 0.00 AC: 0 AN: 14592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.000208 AC: 1 AN: 4798

South Asian (SAS) AF: 0.000443 AC: 2 AN: 4512

European-Finnish (FIN) AF: 0.000312 AC: 3 AN: 9626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000122 AC: 8 AN: 65400

Other (OTH) AF: 0.000985 AC: 2 AN: 2030

⚠️ 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: 0.00108 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00000824 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	0.066
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.5
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.78
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.010
Sift	Benign	0.29	T
Sift4G	Benign	0.16	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.18
MPC		0.060
ClinPred		0.023	T
GERP RS		1.9
Varity_R		0.077
gMVP		0.14
Mutation Taster		=97/3	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: rs145850292; hg19: chr19-7810421; COSMIC: COSV52649215;