rs943036

Variant names:

• chr10-103076290-T-C
• rs943036
• NM_017649.5:c.2418+20T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-103076290-T-C
• chr10-103076290-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017649.5(CNNM2):​c.2418+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,550,844 control chromosomes in the GnomAD database, including 123,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12617 hom., cov: 32)
  • Exomes 𝑓: 0.40 (111123 hom.)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.68
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-103076290-T-C is Benign according to our data. Variant chr10-103076290-T-C is described in ClinVar as Benign. ClinVar VariationId is 1217370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 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.2418+20T>C		intron	N/A	NP_060119.3
	CNNM2	NM_199076.3		c.2352+20T>C		intron	N/A	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.2418+20T>C		intron	N/A	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000970832.1		c.2376+20T>C		intron	N/A	ENSP00000640891.1
	CNNM2	ENST00000433628.2	TSL:2	c.2352+20T>C		intron	N/A	ENSP00000392875.2	Q9H8M5-2

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61500 AN: 151944 Hom.: 12603 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.412

GnomAD2 exomes AF: 0.409 AC: 64855 AN: 158444 AF XY: 0.409

Gnomad AFR exome AF: 0.393

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.492

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.397 AC: 555492 AN: 1398782 Hom.: 111123 Cov.: 32 AF XY: 0.398 AC XY: 274311 AN XY: 689946

African (AFR) AF: 0.386 AC: 12200 AN: 31614

American (AMR) AF: 0.418 AC: 14943 AN: 35730

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 10600 AN: 25188

East Asian (EAS) AF: 0.417 AC: 14940 AN: 35800

South Asian (SAS) AF: 0.407 AC: 32199 AN: 79198

European-Finnish (FIN) AF: 0.366 AC: 18076 AN: 49392

Middle Eastern (MID) AF: 0.438 AC: 2409 AN: 5500

European-Non Finnish (NFE) AF: 0.396 AC: 426510 AN: 1078320

Other (OTH) AF: 0.407 AC: 23615 AN: 58040

GnomAD4 genome AF: 0.405 AC: 61554 AN: 152062 Hom.: 12617 Cov.: 32 AF XY: 0.402 AC XY: 29850 AN XY: 74338

African (AFR) AF: 0.388 AC: 16083 AN: 41474

American (AMR) AF: 0.403 AC: 6160 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1498 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2515 AN: 5174

South Asian (SAS) AF: 0.395 AC: 1902 AN: 4820

European-Finnish (FIN) AF: 0.364 AC: 3846 AN: 10566

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28233 AN: 67970

Other (OTH) AF: 0.415 AC: 873 AN: 2102

Alfa AF: 0.415 Hom.: 6311

Bravo AF: 0.408

Asia WGS AF: 0.403 AC: 1399 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypomagnesemia, seizures, and intellectual disability 1 (1)
-	-	1	Renal hypomagnesemia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.25
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs943036; hg19: chr10-104836047; COSMIC: COSV63998987;