chr10-102919286-C-G

Position:

• chr10-102919286-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain CNNM transmembrane (size 180) in uniprot entity CNNM2_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_017649.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNNM2. . Gene score misZ 4.4105 (greater than the threshold 3.09). Trascript score misZ 5.0056 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	UniProt
CNNM2	NM_017649.5	c.806C>G	p.Ser269Trp	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3	c.806C>G	p.Ser269Trp	missense_variant	1/7
CNNM2	NM_199077.3	c.806C>G	p.Ser269Trp	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.806C>G	p.Ser269Trp	missense_variant	1/8	1	NM_017649.5	P4
CNNM2	ENST00000369875.3	c.806C>G	p.Ser269Trp	missense_variant	1/2	1
CNNM2	ENST00000433628.2	c.806C>G	p.Ser269Trp	missense_variant	1/7	2		A1

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

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -

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
MutationTaster	Benign	1.0	D;D;D;D;D
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;