10-103076162-C-T

Variant names:

• chr10-103076162-C-T
• rs943037
• NM_017649.5:c.2310C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017649.5(CNNM2):​c.2310C>T​(p.Ala770Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,606,540 control chromosomes in the GnomAD database, including 9,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (831 hom., cov: 32)
  • Exomes 𝑓: 0.094 (8374 hom.)
• Consequence: CNNM2 NM_017649.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.35

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 10-103076162-C-T is Benign according to our data. Variant chr10-103076162-C-T is described in ClinVar as [Benign]. Clinvar id is 298649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.2310C>T	p.Ala770Ala	synonymous_variant	Exon 7 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.2244C>T	p.Ala748Ala	synonymous_variant	Exon 6 of 7		NP_951058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.2310C>T	p.Ala770Ala	synonymous_variant	Exon 7 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.2244C>T	p.Ala748Ala	synonymous_variant	Exon 6 of 7	2		ENSP00000392875.2
CNNM2	ENST00000475511.1	n.364C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13375 AN: 152094 Hom.: 826 Cov.: 32

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0746

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0894

Gnomad OTH AF: 0.0997

GnomAD3 exomes AF: 0.124 AC: 29344 AN: 236358 Hom.: 2324 AF XY: 0.124 AC XY: 15794 AN XY: 127760

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.0774

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0945 AC: 137411 AN: 1454328 Hom.: 8374 Cov.: 32 AF XY: 0.0972 AC XY: 70236 AN XY: 722632

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.0753

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0773

Gnomad4 NFE exome AF: 0.0797

Gnomad4 OTH exome AF: 0.0990

GnomAD4 genome AF: 0.0880 AC: 13391 AN: 152212 Hom.: 831 Cov.: 32 AF XY: 0.0903 AC XY: 6722 AN XY: 74418

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.0746

Gnomad4 NFE AF: 0.0894

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0878 Hom.: 476

Bravo AF: 0.0906

Asia WGS AF: 0.195 AC: 677 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypomagnesemia 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.1
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs943037; hg19: chr10-104835919; COSMIC: COSV63997309;