12-7496888-T-C

Position:

• chr12-7496888-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.85 (56630 hom., cov: 32)
  • Exomes 𝑓: 0.94 (655280 hom.)
• Consequence: CD163 NM_203416.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07

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]

ACMG classification

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/exons	MANE	UniProt
CD163	NM_203416.4	c.1024A>G	p.Ile342Val	missense_variant	5/17	ENST00000432237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD163	ENST00000432237.3	c.1024A>G	p.Ile342Val	missense_variant	5/17	1	NM_203416.4	P1

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128998 AN: 152058 Hom.: 56597 Cov.: 32

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

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.: 48 AF XY: 0.943 AC XY: 685551 AN XY: 727174

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.: 32 AF XY: 0.848 AC XY: 63079 AN XY: 74404

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2019	This variant is associated with the following publications: (PMID: 29083407) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.80	T
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	N
LIST_S2	Benign	0.24	T;T;T;T
MetaRNN	Benign	0.0000017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs4883263; hg19: chr12-7649484; COSMIC: COSV63136434;