1-196949475-A-G

Position:

chr1-196949475-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_005666.4(CFHR2):c.79A>G(p.Lys27Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

CFHR2
NM_005666.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.26

Variant links:

Genes affected

CFHR2 (HGNC:4890): (complement factor H related 2) This gene belongs to a family of complement factor H-related genes (CFHR), which are clustered together with complement factor H gene on chromosome 1, and are involved in regulation of complement. Mutations in CFHR genes have been associated with dense deposit disease and atypical haemolytic-uraemic syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

CFHR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 1-196949475-A-G is Benign according to our data. Variant chr1-196949475-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2637659.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR2	NM_005666.4 linkuse as main transcript	c.79A>G	p.Lys27Glu	missense_variant	2/5	ENST00000367415.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR2	ENST00000367415.8 linkuse as main transcript	c.79A>G	p.Lys27Glu	missense_variant	2/5	1	NM_005666.4	P2	P36980-1

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000204

AC:

AN:

250268

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.000407

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1460946

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

726764

show subpopulations

Gnomad4 AFR exome

AF:

0.00258

Gnomad4 AMR exome

AF:

0.000494

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152322

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000495

Hom.:

Bravo

AF:

0.000975

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 02, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 10, 2023

Variant summary: CFHR2 c.79A>G (p.Lys27Glu) results in a conservative amino acid change located in the Sushi/SCR/CCP domain (IPR000436) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250268 control chromosomes, predominantly at a frequency of 0.0023 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFHR2 causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.79A>G in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.16

DEOGEN2

Benign

0.0016

.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.52

T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.64

.;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.090

.;N;.

REVEL

Benign

0.028

Sift

Benign

1.0

.;T;.

Sift4G

Benign

0.93

.;T;T

Polyphen

0.044

.;B;.

Vest4

0.090, 0.13

MVP

0.28

MPC

0.0090

ClinPred

0.012

GERP RS

-2.2

Varity_R

0.062

gMVP

0.085

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.74

Position offset: 1

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