rs943036

chr10-103076290-T-C

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -2.68

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 -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 id is 1217370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-103076290-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM2	NM_017649.5	c.2418+20T>C		intron_variant		ENST00000369878.9
CNNM2	NM_199076.3	c.2352+20T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.2418+20T>C		intron_variant		1	NM_017649.5	P4
CNNM2	ENST00000433628.2	c.2352+20T>C		intron_variant		2		A1
CNNM2	ENST00000475511.1	n.472+20T>C		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.409 AC: 64855 AN: 158444 Hom.: 13286 AF XY: 0.409 AC XY: 34169 AN XY: 83540

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 SAS exome AF: 0.402

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

Gnomad4 AFR exome AF: 0.386

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.407

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

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.415

Alfa AF: 0.413 Hom.: 2892

Bravo AF: 0.408

Asia WGS AF: 0.403 AC: 1399 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomagnesemia, seizures, and intellectual disability 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Renal hypomagnesemia 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.2
Dann	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs943036; hg19: chr10-104836047; COSMIC: COSV63998987;