10-103076754-A-G

Variant names:

• chr10-103076754-A-G
• rs2296569
• NM_017649.5:c.2419-217A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017649.5(CNNM2):​c.2419-217A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,226 control chromosomes in the GnomAD database, including 1,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1532 hom., cov: 32)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.357
• Publications: 14 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, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-103076754-A-G is Benign according to our data. Variant chr10-103076754-A-G is described in ClinVar as Benign. ClinVar VariationId is 1243956.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.2419-217A>G		intron_variant	Intron 7 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.2353-217A>G		intron_variant	Intron 6 of 6		NP_951058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.2419-217A>G		intron_variant	Intron 7 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.2353-217A>G		intron_variant	Intron 6 of 6	2		ENSP00000392875.2
CNNM2	ENST00000475511.1	n.473-217A>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18787 AN: 152108 Hom.: 1533 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0843

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.0990

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18778 AN: 152226 Hom.: 1532 Cov.: 32 AF XY: 0.122 AC XY: 9085 AN XY: 74418

African (AFR) AF: 0.0321 AC: 1335 AN: 41552

American (AMR) AF: 0.105 AC: 1609 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 412 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5186

South Asian (SAS) AF: 0.0842 AC: 406 AN: 4822

European-Finnish (FIN) AF: 0.199 AC: 2113 AN: 10596

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12556 AN: 67988

Other (OTH) AF: 0.0980 AC: 207 AN: 2112

Alfa AF: 0.159 Hom.: 3990

Bravo AF: 0.111

Asia WGS AF: 0.0390 AC: 139 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	10
DANN	Benign	0.58
PhyloP100		0.36
Mutation Taster		=100/0	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: rs2296569; hg19: chr10-104836511;