NM_017649.5:c.113G>A

Variant names:

• chr10-102918593-G-A
• rs76057237
• NM_017649.5:c.113G>A

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.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,564,724 control chromosomes in the GnomAD database, including 2,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.048 (182 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2012 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.46
• Publications: 12 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, ClinGen
• 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 (MetaRNN=0.0015188456).
• BP6: Variant 10-102918593-G-A is Benign according to our data. Variant chr10-102918593-G-A is described in ClinVar as Benign. ClinVar VariationId is 298635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 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.113G>A	p.Arg38Gln	missense	Exon 1 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.113G>A	p.Arg38Gln	missense	Exon 1 of 7	NP_951058.1	Q9H8M5-2
	CNNM2	NM_199077.3		c.113G>A	p.Arg38Gln	missense	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.113G>A	p.Arg38Gln	missense	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000369875.3	TSL:1	c.113G>A	p.Arg38Gln	missense	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
	CNNM2	ENST00000970832.1		c.113G>A	p.Arg38Gln	missense	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7366 AN: 152116 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0479

GnomAD2 exomes AF: 0.0419 AC: 6884 AN: 164396 AF XY: 0.0414

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0604

Gnomad NFE exome AF: 0.0587

Gnomad OTH exome AF: 0.0468

GnomAD4 exome AF: 0.0504 AC: 71153 AN: 1412494 Hom.: 2012 Cov.: 32 AF XY: 0.0494 AC XY: 34539 AN XY: 699284

African (AFR) AF: 0.0493 AC: 1505 AN: 30540

American (AMR) AF: 0.0265 AC: 993 AN: 37484

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 776 AN: 24882

East Asian (EAS) AF: 0.000192 AC: 7 AN: 36406

South Asian (SAS) AF: 0.0179 AC: 1451 AN: 80874

European-Finnish (FIN) AF: 0.0584 AC: 2802 AN: 48012

Middle Eastern (MID) AF: 0.0247 AC: 127 AN: 5152

European-Non Finnish (NFE) AF: 0.0558 AC: 60812 AN: 1090678

Other (OTH) AF: 0.0458 AC: 2680 AN: 58466

GnomAD4 genome AF: 0.0485 AC: 7378 AN: 152230 Hom.: 182 Cov.: 32 AF XY: 0.0472 AC XY: 3515 AN XY: 74426

African (AFR) AF: 0.0455 AC: 1892 AN: 41558

American (AMR) AF: 0.0335 AC: 513 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4830

European-Finnish (FIN) AF: 0.0633 AC: 671 AN: 10602

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0567 AC: 3851 AN: 67978

Other (OTH) AF: 0.0493 AC: 104 AN: 2110

Alfa AF: 0.0490 Hom.: 50

Bravo AF: 0.0456

TwinsUK AF: 0.0483 AC: 179

ALSPAC AF: 0.0488 AC: 188

ESP6500AA AF: 0.0342 AC: 128

ESP6500EA AF: 0.0469 AC: 346

ExAC AF: 0.0343 AC: 3804

Asia WGS AF: 0.0160 AC: 57 AN: 3474

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.79	P
Vest4		0.040
ClinPred		0.088	T
GERP RS		4.1
PromoterAI		-0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.23
gMVP		0.39
Mutation Taster		=86/14	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: rs76057237; hg19: chr10-104678350; COSMIC: COSV63996349; COSMIC: COSV63996349;