rs532564685

Variant names:

• chr10-102918586-C-A
• rs532564685
• NM_017649.5:c.106C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-102918586-C-A
• chr10-102918586-C-G
• chr10-102918586-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017649.5(CNNM2):​c.106C>A​(p.Arg36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.627
• Publications: 0 publications found

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]

CNNM2 Gene-Disease associations (from GenCC):

• hypomagnesemia, seizures, and intellectual disability 1

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• renal hypomagnesemia 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial primary hypomagnesemia with normocalciuria and normocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23513946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.106C>A	p.Arg36Ser	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.106C>A	p.Arg36Ser	missense_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.106C>A	p.Arg36Ser	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.106C>A	p.Arg36Ser	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.106C>A	p.Arg36Ser	missense_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.106C>A	p.Arg36Ser	missense_variant	Exon 1 of 7	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 703270

African (AFR) AF: 0.00 AC: 0 AN: 30532

American (AMR) AF: 0.00 AC: 0 AN: 38488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24960

East Asian (EAS) AF: 0.00 AC: 0 AN: 36674

South Asian (SAS) AF: 0.00 AC: 0 AN: 81434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5226

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1094470

Other (OTH) AF: 0.00 AC: 0 AN: 58700

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		0.63
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.38	T;T;T
Polyphen		0.011	B;.;B
Vest4		0.22
MutPred		0.34		Gain of glycosylation at R36 (P = 0.0022);Gain of glycosylation at R36 (P = 0.0022);Gain of glycosylation at R36 (P = 0.0022);
MVP		0.043
ClinPred		0.36	T
GERP RS		4.2
PromoterAI		-0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.47
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs532564685; hg19: chr10-104678343;