1-196949608-C-T

Variant names:

• chr1-196949608-C-T
• rs144096230
• NM_005666.4:c.212C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005666.4(CFHR2):​c.212C>T​(p.Thr71Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,613,916 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T71T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (36 hom.)
• Consequence: CFHR2 NM_005666.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.18
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028270662).
• BP6: Variant 1-196949608-C-T is Benign according to our data. Variant chr1-196949608-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1712465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR2	NM_005666.4	MANE Select	c.212C>T	p.Thr71Met	missense	Exon 2 of 5	NP_005657.1	P36980-1
	CFHR2	NM_001410924.1		c.59-1244C>T		intron	N/A	NP_001397853.1	A0A3B3IRW0
	CFHR2	NM_001312672.1		c.58+5670C>T		intron	N/A	NP_001299601.1	A0A3B3IS28

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR2	ENST00000367415.8	TSL:1 MANE Select	c.212C>T	p.Thr71Met	missense	Exon 2 of 5	ENSP00000356385.4	P36980-1
	CFHR2	ENST00000367421.5	TSL:1	c.467C>T	p.Thr156Met	missense	Exon 3 of 6	ENSP00000356391.4	A0A3B3IQ51
	CFHR2	ENST00000473386.1	TSL:1	c.58+5670C>T		intron	N/A	ENSP00000497089.1	A0A3B3IS28

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 152162 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00365 AC: 916 AN: 251228 AF XY: 0.00389

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00560

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00487 AC: 7124 AN: 1461636 Hom.: 36 Cov.: 31 AF XY: 0.00493 AC XY: 3584 AN XY: 727118

African (AFR) AF: 0.000807 AC: 27 AN: 33466

American (AMR) AF: 0.00128 AC: 57 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00443 AC: 382 AN: 86254

European-Finnish (FIN) AF: 0.00653 AC: 349 AN: 53416

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.00545 AC: 6059 AN: 1111868

Other (OTH) AF: 0.00386 AC: 233 AN: 60384

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152280 Hom.: 3 Cov.: 33 AF XY: 0.00363 AC XY: 270 AN XY: 74474

African (AFR) AF: 0.000674 AC: 28 AN: 41552

American (AMR) AF: 0.000915 AC: 14 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00681 AC: 463 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00549 Hom.: 3

Bravo AF: 0.00312

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00396 AC: 481

EpiCase AF: 0.00507

EpiControl AF: 0.00450

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.038
DANN	Benign	0.81
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		-2.2
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.11
Sift	Benign	0.039	D
Sift4G	Benign	0.27	T
Polyphen		0.21	B
Vest4		0.15
MVP		0.39
MPC		0.022
ClinPred		0.019	T
GERP RS		-1.6
Varity_R		0.030
gMVP		0.26
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144096230; hg19: chr1-196918738; COSMIC: COSV66381091;