rs794726858

Variant names:

• chr10-102919286-C-G
• rs794726858
• NM_017649.5:c.806C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_017649.5(CNNM2):​c.806C>G​(p.Ser269Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.89

Genes affected

CNNM2 (HGNC:103): (cyclin and CBS domain divalent metal cation transport mediator 2) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg2+. Mutations in this gene are associated with renal hypomagnesemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CNNM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.4105 (above the threshold of 3.09). Trascript score misZ: 5.0056 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomagnesemia, seizures, and intellectual disability 1, familial primary hypomagnesemia with normocalciuria and normocalcemia, renal hypomagnesemia 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 10-102919286-C-G is Pathogenic according to our data. Variant chr10-102919286-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192325.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.806C>G	p.Ser269Trp	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.806C>G	p.Ser269Trp	missense_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.806C>G	p.Ser269Trp	missense_variant	Exon 1 of 2		NP_951059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.806C>G	p.Ser269Trp	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.806C>G	p.Ser269Trp	missense_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.806C>G	p.Ser269Trp	missense_variant	Exon 1 of 7	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomagnesemia, seizures, and intellectual disability 1 Pathogenic:2

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Hypomagnesemia, seizures, and mental retardation, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24699222). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:24699222). -

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MutPred		0.83		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.82
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794726858; hg19: chr10-104679043; COSMIC: COSV63996518; COSMIC: COSV63996518;