10-102918600-C-T

Variant names:

• chr10-102918600-C-T
• rs1845507943
• NM_017649.5:c.120C>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.120C>T​(p.Ile40Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,080 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000014 (0 hom.)
• Consequence: CNNM2 NM_017649.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.200
• 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

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=-0.49).
• BP6: Variant 10-102918600-C-T is Benign according to our data. Variant chr10-102918600-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1536780.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.2 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.120C>T	p.Ile40Ile	synonymous	Exon 1 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.120C>T	p.Ile40Ile	synonymous	Exon 1 of 7	NP_951058.1	Q9H8M5-2
	CNNM2	NM_199077.3		c.120C>T	p.Ile40Ile	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.120C>T	p.Ile40Ile	synonymous	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000369875.3	TSL:1	c.120C>T	p.Ile40Ile	synonymous	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
	CNNM2	ENST00000970832.1		c.120C>T	p.Ile40Ile	synonymous	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407080 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 696134

African (AFR) AF: 0.00 AC: 0 AN: 30388

American (AMR) AF: 0.00 AC: 0 AN: 36646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24768

East Asian (EAS) AF: 0.00 AC: 0 AN: 36052

South Asian (SAS) AF: 0.00 AC: 0 AN: 80338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5120

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1087502

Other (OTH) AF: 0.00 AC: 0 AN: 58246

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	-0.49
CADD	Benign	11
DANN	Benign	0.96
PhyloP100		0.20
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs1845507943; hg19: chr10-104678357;