1-207609571-A-T

Variant names:

• chr1-207609571-A-T
• rs4844609
• NM_000651.6:c.6178A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000651.6(CR1):​c.6178A>T​(p.Thr2060Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,613,696 control chromosomes in the GnomAD database, including 774,762 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.99 (73972 hom., cov: 31)
  • Exomes 𝑓: 0.98 (700790 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.871
• Publications: 81 publications found

Genes affected

CR1 (HGNC:2334): (complement C3b/C4b receptor 1 (Knops blood group)) This gene is a member of the receptors of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The genome is polymorphic at this locus with allele-specific splice variants encoding different isoforms, based on the presence/absence of long homologous repeats (LHRs). The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in this gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus, sarcoidosis and Alzheimer's disease. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum rosetting, conferring protection against severe malaria. [provided by RefSeq, May 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.904434E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000651.6. 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
	CR1	NM_000651.6	MANE Select	c.6178A>T	p.Thr2060Ser	missense	Exon 37 of 47	NP_000642.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR1	ENST00000367049.9	TSL:5 MANE Select	c.6178A>T	p.Thr2060Ser	missense	Exon 37 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.4828A>T	p.Thr1610Ser	missense	Exon 29 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.4828A>T	p.Thr1610Ser	missense	Exon 29 of 39	ENSP00000356018.1	P17927

Frequencies

GnomAD3 genomes AF: 0.986 AC: 149966 AN: 152168 Hom.: 73913 Cov.: 31

Gnomad AFR AF: 0.995

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.989

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.975

Gnomad OTH AF: 0.993

GnomAD2 exomes AF: 0.985 AC: 244723 AN: 248328 AF XY: 0.986

Gnomad AFR exome AF: 0.997

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.990

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.986

Gnomad NFE exome AF: 0.976

Gnomad OTH exome AF: 0.987

GnomAD4 exome AF: 0.979 AC: 1431126 AN: 1461410 Hom.: 700790 Cov.: 58 AF XY: 0.980 AC XY: 712096 AN XY: 726942

African (AFR) AF: 0.997 AC: 33385 AN: 33478

American (AMR) AF: 0.992 AC: 44315 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.990 AC: 25864 AN: 26120

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 0.997 AC: 85899 AN: 86190

European-Finnish (FIN) AF: 0.985 AC: 52611 AN: 53396

Middle Eastern (MID) AF: 0.998 AC: 5755 AN: 5768

European-Non Finnish (NFE) AF: 0.975 AC: 1084143 AN: 1111724

Other (OTH) AF: 0.985 AC: 59456 AN: 60366

GnomAD4 genome AF: 0.986 AC: 150084 AN: 152286 Hom.: 73972 Cov.: 31 AF XY: 0.987 AC XY: 73463 AN XY: 74462

African (AFR) AF: 0.995 AC: 41351 AN: 41538

American (AMR) AF: 0.992 AC: 15179 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3432 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5175 AN: 5176

South Asian (SAS) AF: 0.998 AC: 4812 AN: 4824

European-Finnish (FIN) AF: 0.989 AC: 10499 AN: 10620

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.975 AC: 66334 AN: 68036

Other (OTH) AF: 0.993 AC: 2099 AN: 2114

Alfa AF: 0.978 Hom.: 54957

Bravo AF: 0.986

TwinsUK AF: 0.973 AC: 3607

ALSPAC AF: 0.980 AC: 3775

ESP6500AA AF: 0.996 AC: 3818

ESP6500EA AF: 0.975 AC: 8041

ExAC AF: 0.985 AC: 119016

Asia WGS AF: 0.998 AC: 3471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.23
DANN	Benign	0.13
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00017	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.87
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.084
Sift	Benign	0.80	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.019
MutPred		0.54		Loss of stability (P = 0.1743)
MPC		0.099
ClinPred		0.0016	T
GERP RS		2.5
gMVP		0.22
Mutation Taster		=99/1	polymorphism (auto)

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: rs4844609; hg19: chr1-207782916; COSMIC: COSV107457945; COSMIC: COSV107457945;