1-207611623-A-G

Variant names:

• chr1-207611623-A-G
• rs3818361
• NM_000651.6:c.6296-54A>G

Variant summary

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

The NM_000651.6(CR1):​c.6296-54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,600,796 control chromosomes in the GnomAD database, including 519,288 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (43249 hom., cov: 31)
  • Exomes 𝑓: 0.81 (476039 hom.)
• Consequence: CR1 NM_000651.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138
• Publications: 186 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 (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.6296-54A>G		intron_variant	Intron 37 of 46	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.6296-54A>G		intron_variant	Intron 37 of 46	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113399 AN: 151866 Hom.: 43226 Cov.: 31

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.830

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.778

GnomAD4 exome AF: 0.809 AC: 1171593 AN: 1448812 Hom.: 476039 AF XY: 0.811 AC XY: 583921 AN XY: 719838

African (AFR) AF: 0.582 AC: 19305 AN: 33184

American (AMR) AF: 0.888 AC: 38842 AN: 43728

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 20136 AN: 24868

East Asian (EAS) AF: 0.637 AC: 25238 AN: 39646

South Asian (SAS) AF: 0.894 AC: 75034 AN: 83912

European-Finnish (FIN) AF: 0.806 AC: 42532 AN: 52754

Middle Eastern (MID) AF: 0.823 AC: 4669 AN: 5672

European-Non Finnish (NFE) AF: 0.813 AC: 898162 AN: 1105262

Other (OTH) AF: 0.797 AC: 47675 AN: 59786

GnomAD4 genome AF: 0.747 AC: 113469 AN: 151984 Hom.: 43249 Cov.: 31 AF XY: 0.751 AC XY: 55766 AN XY: 74298

African (AFR) AF: 0.591 AC: 24450 AN: 41378

American (AMR) AF: 0.831 AC: 12694 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 2800 AN: 3470

East Asian (EAS) AF: 0.655 AC: 3379 AN: 5162

South Asian (SAS) AF: 0.896 AC: 4314 AN: 4814

European-Finnish (FIN) AF: 0.808 AC: 8534 AN: 10558

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54695 AN: 68002

Other (OTH) AF: 0.777 AC: 1642 AN: 2112

Alfa AF: 0.788 Hom.: 229114

Bravo AF: 0.740

Asia WGS AF: 0.795 AC: 2766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.2
DANN	Benign	0.32
PhyloP100		0.14
Mutation Taster		=100/0	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: rs3818361; hg19: chr1-207784968;