NM_017649.5:c.2310C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 45 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: Benign. The variant received -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 VariationId 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.

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.2310C>T	p.Ala770Ala	synonymous	Exon 7 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.2244C>T	p.Ala748Ala	synonymous	Exon 6 of 7	NP_951058.1	Q9H8M5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.2310C>T	p.Ala770Ala	synonymous	Exon 7 of 8	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000970832.1		c.2268C>T	p.Ala756Ala	synonymous	Exon 6 of 7	ENSP00000640891.1
	CNNM2	ENST00000433628.2	TSL:2	c.2244C>T	p.Ala748Ala	synonymous	Exon 6 of 7	ENSP00000392875.2	Q9H8M5-2

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

GnomAD2 exomes AF: 0.124 AC: 29344 AN: 236358 AF XY: 0.124

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 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

African (AFR) AF: 0.0322 AC: 1075 AN: 33362

American (AMR) AF: 0.199 AC: 8627 AN: 43350

Ashkenazi Jewish (ASJ) AF: 0.0753 AC: 1957 AN: 25988

East Asian (EAS) AF: 0.261 AC: 10297 AN: 39388

South Asian (SAS) AF: 0.196 AC: 16554 AN: 84574

European-Finnish (FIN) AF: 0.0773 AC: 4095 AN: 52978

Middle Eastern (MID) AF: 0.0866 AC: 499 AN: 5762

European-Non Finnish (NFE) AF: 0.0797 AC: 88353 AN: 1108762

Other (OTH) AF: 0.0990 AC: 5954 AN: 60164

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

African (AFR) AF: 0.0393 AC: 1634 AN: 41556

American (AMR) AF: 0.135 AC: 2067 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3472

East Asian (EAS) AF: 0.278 AC: 1438 AN: 5180

South Asian (SAS) AF: 0.184 AC: 887 AN: 4818

European-Finnish (FIN) AF: 0.0746 AC: 790 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0894 AC: 6080 AN: 67992

Other (OTH) AF: 0.102 AC: 216 AN: 2108

Alfa AF: 0.0835 Hom.: 555

Bravo AF: 0.0906

Asia WGS AF: 0.195 AC: 677 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Renal hypomagnesemia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-3.3
Mutation Taster		=99/1	polymorphism (auto)

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