10-102918576-C-T

Variant names:

• chr10-102918576-C-T
• NM_017649.5:c.96C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_017649.5(CNNM2):​c.96C>T​(p.Ser32Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNNM2 NM_017649.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.454
• 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: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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

ENSG00000286575 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-102918576-C-T is Benign according to our data. Variant chr10-102918576-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3651227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.454 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017649.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	NM_017649.5	MANE Select	c.96C>T	p.Ser32Ser	synonymous	Exon 1 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.96C>T	p.Ser32Ser	synonymous	Exon 1 of 7	NP_951058.1	Q9H8M5-2
	CNNM2	NM_199077.3		c.96C>T	p.Ser32Ser	synonymous	Exon 1 of 2	NP_951059.1	Q9H8M5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.96C>T	p.Ser32Ser	synonymous	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000369875.3	TSL:1	c.96C>T	p.Ser32Ser	synonymous	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
	CNNM2	ENST00000970832.1		c.96C>T	p.Ser32Ser	synonymous	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426958 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 708152

African (AFR) AF: 0.00 AC: 0 AN: 30650

American (AMR) AF: 0.00 AC: 0 AN: 39918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 37016

South Asian (SAS) AF: 0.00 AC: 0 AN: 82324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098820

Other (OTH) AF: 0.00 AC: 0 AN: 58982

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		0.45
PromoterAI		-0.023	Neutral

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

hg19: chr10-104678333; COSMIC: COSV63996221;