Genetic Variant CFHR2:p.Thr71Lys (chr1-196949608-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005666.4(CFHR2):c.212C>A(p.Thr71Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T71M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CFHR2
NM_005666.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.18

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005666.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFHR2	NM_005666.4	MANE Select	c.212C>A	p.Thr71Lys	missense	Exon 2 of 5	NP_005657.1	P36980-1
CFHR2	NM_001410924.1		c.59-1244C>A		intron	N/A	NP_001397853.1	A0A3B3IRW0
CFHR2	NM_001312672.1		c.58+5670C>A		intron	N/A	NP_001299601.1	A0A3B3IS28

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFHR2	ENST00000367415.8	TSL:1 MANE Select	c.212C>A	p.Thr71Lys	missense	Exon 2 of 5	ENSP00000356385.4	P36980-1
CFHR2	ENST00000367421.5	TSL:1	c.467C>A	p.Thr156Lys	missense	Exon 3 of 6	ENSP00000356391.4	A0A3B3IQ51
CFHR2	ENST00000473386.1	TSL:1	c.58+5670C>A		intron	N/A	ENSP00000497089.1	A0A3B3IS28

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111878

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.21

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.012

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.61

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.84

MutationAssessor

Benign

2.0

PhyloP100

-2.2

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.4

REVEL

Uncertain

0.30

Sift

Benign

0.45

Sift4G

Benign

0.50

Polyphen

0.68

Vest4

0.27

MutPred

0.78

Gain of methylation at T71 (P = 0.0082)

MVP

0.53

MPC

0.022

ClinPred

0.51

GERP RS

-1.6

Varity_R

0.074

gMVP

0.28

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over