Genetic Variant CD163:p.Ile342Val (chr12-7496888-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203416.4(CD163):c.1024A>G(p.Ile342Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.934 in 1,613,920 control chromosomes in the GnomAD database, including 711,910 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.85 ( 56630 hom., cov: 32)

Exomes 𝑓: 0.94 ( 655280 hom. )

Consequence

CD163
NM_203416.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.07

Variant links:

Genes affected

CD163 (HGNC:1631): (CD163 molecule) The protein encoded by this gene is a member of the scavenger receptor cysteine-rich (SRCR) superfamily, and is exclusively expressed in monocytes and macrophages. It functions as an acute phase-regulated receptor involved in the clearance and endocytosis of hemoglobin/haptoglobin complexes by macrophages, and may thereby protect tissues from free hemoglobin-mediated oxidative damage. This protein may also function as an innate immune sensor for bacteria and inducer of local inflammation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

CD163 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6509773E-6).

BP6

Variant 12-7496888-T-C is Benign according to our data. Variant chr12-7496888-T-C is described in ClinVar as [Benign]. Clinvar id is 1253566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD163	NM_203416.4 link	c.1024A>G	p.Ile342Val	missense_variant	Exon 5 of 17	ENST00000432237.3	NP_981961.2	Q86VB7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD163	ENST00000432237.3 link	c.1024A>G	p.Ile342Val	missense_variant	Exon 5 of 17	1	NM_203416.4	ENSP00000403885.2		Q86VB7-3

Frequencies

GnomAD3 genomes

AF:

0.848

AC:

128998

AN:

152058

Hom.:

56597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.618

Gnomad AMI

AF:

0.984

Gnomad AMR

AF:

0.853

Gnomad ASJ

AF:

0.973

Gnomad EAS

AF:

0.706

Gnomad SAS

AF:

0.850

Gnomad FIN

AF:

0.972

Gnomad MID

AF:

0.930

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.869

GnomAD3 exomes

AF:

0.889

AC:

223003

AN:

250984

Hom.:

100860

AF XY:

0.898

AC XY:

121771

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.604

Gnomad AMR exome

AF:

0.805

Gnomad ASJ exome

AF:

0.973

Gnomad EAS exome

AF:

0.691

Gnomad SAS exome

AF:

0.857

Gnomad FIN exome

AF:

0.974

Gnomad NFE exome

AF:

0.969

Gnomad OTH exome

AF:

0.924

GnomAD4 exome

AF:

0.943

AC:

1379100

AN:

1461744

Hom.:

655280

Cov.:

AF XY:

0.943

AC XY:

685551

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.602

Gnomad4 AMR exome

AF:

0.810

Gnomad4 ASJ exome

AF:

0.974

Gnomad4 EAS exome

AF:

0.721

Gnomad4 SAS exome

AF:

0.860

Gnomad4 FIN exome

AF:

0.972

Gnomad4 NFE exome

AF:

0.973

Gnomad4 OTH exome

AF:

0.924

GnomAD4 genome

AF:

0.848

AC:

129096

AN:

152176

Hom.:

56630

Cov.:

AF XY:

0.848

AC XY:

63079

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.619

Gnomad4 AMR

AF:

0.853

Gnomad4 ASJ

AF:

0.973

Gnomad4 EAS

AF:

0.706

Gnomad4 SAS

AF:

0.850

Gnomad4 FIN

AF:

0.972

Gnomad4 NFE

AF:

0.969

Gnomad4 OTH

AF:

0.870

Alfa

AF:

0.941

Hom.:

170161

Bravo

AF:

0.827

TwinsUK

AF:

0.970

AC:

3598

ALSPAC

AF:

0.975

AC:

3756

ESP6500AA

AF:

0.626

AC:

2759

ESP6500EA

AF:

0.968

AC:

8324

ExAC

AF:

0.887

AC:

107673

Asia WGS

AF:

0.797

AC:

2773

AN:

3478

EpiCase

AF:

0.966

EpiControl

AF:

0.968

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29083407) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.062

DANN

Benign

0.51

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.24

T;T;T;T

MetaRNN

Benign

0.0000017

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;.;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.52

N;N;N;N

REVEL

Benign

0.026

Sift

Benign

0.20

T;T;T;T

Sift4G

Uncertain

0.033

D;D;D;D

Polyphen

0.0040

B;.;B;B

Vest4

0.065

MPC

0.37

ClinPred

0.0027

GERP RS

-1.5

Varity_R

0.033

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over