rs375905519

Variant names:

• chr1-196950930-AAATT-A
• rs375905519
• NM_005666.4:c.334_337delATTA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005666.4(CFHR2):​c.334_337delATTA​(p.Ile112PhefsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,614,142 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (7 hom.)
• Consequence: CFHR2 NM_005666.4 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.792
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 1-196950930-AAATT-A is Benign according to our data. Variant chr1-196950930-AAATT-A is described in ClinVar as Benign. ClinVar VariationId is 732212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000788 (120/152344) while in subpopulation EAS AF = 0.0212 (110/5188). AF 95% confidence interval is 0.018. There are 2 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.334_337delATTA	p.Ile112PhefsTer18	frameshift	Exon 3 of 5	NP_005657.1	P36980-1
	CFHR2	NM_001410924.1		c.139_142delATTA	p.Ile47PhefsTer18	frameshift	Exon 2 of 4	NP_001397853.1	A0A3B3IRW0
	CFHR2	NM_001312672.1		c.59-6959_59-6956delATTA		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.334_337delATTA	p.Ile112PhefsTer18	frameshift	Exon 3 of 5	ENSP00000356385.4	P36980-1
	CFHR2	ENST00000367421.5	TSL:1	c.589_592delATTA	p.Ile197PhefsTer18	frameshift	Exon 4 of 6	ENSP00000356391.4	A0A3B3IQ51
	CFHR2	ENST00000473386.1	TSL:1	c.59-6959_59-6956delATTA		intron	N/A	ENSP00000497089.1	A0A3B3IS28

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152226 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0213

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00145 AC: 364 AN: 251246 AF XY: 0.00127

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000520 AC: 760 AN: 1461798 Hom.: 7 AF XY: 0.000524 AC XY: 381 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0166 AC: 659 AN: 39692

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.000629 AC: 38 AN: 60386

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152344 Hom.: 2 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0212 AC: 110 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000729

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=184/16	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs375905519; hg19: chr1-196920060; COSMIC: COSV66381382;