1-207761332-G-C

Position:

• chr1-207761332-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_172351.3(CD46):​c.559G>C​(p.Val187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CD46 NM_172351.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.44

Genes affected

CD46 (HGNC:6953): (CD46 molecule) The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system. The encoded protein has cofactor activity for inactivation of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement. In addition, the encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6, and type IV pili of pathogenic Neisseria. Finally, the protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization. Mutations at this locus have been associated with susceptibility to hemolytic uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

MIR29B2CHG (HGNC:32018): (MIR29B2 and MIR29C host gene)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 1-207761332-G-C is Pathogenic according to our data. Variant chr1-207761332-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3068272.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD46	NM_172351.3	c.559G>C	p.Val187Leu	missense_variant	5/13	ENST00000367042.6	NP_758861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6	c.559G>C	p.Val187Leu	missense_variant	5/13	1	NM_172351.3	ENSP00000356009	A2
MIR29B2CHG	ENST00000710901.1	n.2319C>G		non_coding_transcript_exon_variant	6/6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;M;M;M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D
Polyphen		0.93	P;D;D;D;P;D;D;.;D;P
Vest4		0.70
MutPred		0.76		Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);.;Loss of glycosylation at S190 (P = 0.2018);Loss of glycosylation at S190 (P = 0.2018);
MVP		0.61
MPC		0.59
ClinPred		0.92	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-207934677;