10-102918580-A-C

Variant names:

• chr10-102918580-A-C
• NM_017649.5:c.100A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_017649.5(CNNM2):​c.100A>C​(p.Ser34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,424,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

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]

ENSG00000286575 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15758097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.100A>C	p.Ser34Arg	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.100A>C	p.Ser34Arg	missense_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.100A>C	p.Ser34Arg	missense_variant	Exon 1 of 2		NP_951059.1
LOC107984265	NR_160733.1	n.-245T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.100A>C	p.Ser34Arg	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.100A>C	p.Ser34Arg	missense_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.100A>C	p.Ser34Arg	missense_variant	Exon 1 of 7	2		ENSP00000392875.2
ENSG00000286575	ENST00000652934.1	n.-245T>G		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1424144 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.096	T;T;T
Polyphen		0.072	B;.;B
Vest4		0.20
MutPred		0.29		Gain of methylation at S34 (P = 0.0178);Gain of methylation at S34 (P = 0.0178);Gain of methylation at S34 (P = 0.0178);
MVP		0.068
ClinPred		0.13	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr10-104678337;