1-196950923-A-G

Position:

• chr1-196950923-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005666.4(CFHR2):​c.325A>G​(p.Thr109Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,614,062 control chromosomes in the GnomAD database, including 48 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (44 hom.)
• Consequence: CFHR2 NM_005666.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.161

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013218045).
• BP6: Variant 1-196950923-A-G is Benign according to our data. Variant chr1-196950923-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 708283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196950923-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR2	NM_005666.4	c.325A>G	p.Thr109Ala	missense_variant	3/5	ENST00000367415.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR2	ENST00000367415.8	c.325A>G	p.Thr109Ala	missense_variant	3/5	1	NM_005666.4	P2

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 847 AN: 152178 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00832

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00567 AC: 1425 AN: 251212 Hom.: 5 AF XY: 0.00574 AC XY: 779 AN XY: 135764

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00699 AC: 10216 AN: 1461766 Hom.: 44 Cov.: 31 AF XY: 0.00693 AC XY: 5042 AN XY: 727174

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.00787

Gnomad4 OTH exome AF: 0.00633

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152296 Hom.: 4 Cov.: 33 AF XY: 0.00575 AC XY: 428 AN XY: 74468

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00832

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00622 Hom.: 3

Bravo AF: 0.00454

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00594 AC: 721

EpiCase AF: 0.00812

EpiControl AF: 0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CFHR2: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.0
DANN	Benign	0.94
DEOGEN2	Benign	0.0071	.;T;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.44	T;T;T;T;T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	.;M;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	.;N;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.082	.;T;.;.;.
Sift4G	Benign	0.29	.;T;.;T;.
Polyphen		0.99	.;D;.;.;.
Vest4		0.047, 0.10
MVP		0.54
MPC		0.026
ClinPred		0.018	T
GERP RS		-1.2
Varity_R		0.052
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs145405649; hg19: chr1-196920053;