10-103089359-G-C

Variant names:

• chr10-103089359-G-C
• rs10786736
• NM_017649.5:c.*12179G>C

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.*12179G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 277,202 control chromosomes in the GnomAD database, including 2,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1063 hom., cov: 32)
  • Exomes 𝑓: 0.13 (1236 hom.)
• Consequence: CNNM2 NM_017649.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.275
• Publications: 29 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]

NT5C2 (HGNC:8022): (5'-nucleotidase, cytosolic II) This gene encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. [provided by RefSeq, Oct 2011]

NT5C2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 45

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-103089359-G-C is Benign according to our data. Variant chr10-103089359-G-C is described in ClinVar as Benign. ClinVar VariationId is 1168446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	NM_017649.5	MANE Select	c.*12179G>C		3_prime_UTR	Exon 8 of 8	NP_060119.3
	NT5C2	NM_001351169.2	MANE Select	c.*313C>G		3_prime_UTR	Exon 19 of 19	NP_001338098.1
	CNNM2	NM_199076.3		c.*12179G>C		3_prime_UTR	Exon 7 of 7	NP_951058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.*12179G>C		3_prime_UTR	Exon 8 of 8	ENSP00000358894.3
	NT5C2	ENST00000404739.8	TSL:1 MANE Select	c.*313C>G		3_prime_UTR	Exon 19 of 19	ENSP00000383960.3
	NT5C2	ENST00000343289.9	TSL:1	c.*313C>G		3_prime_UTR	Exon 18 of 18	ENSP00000339479.5

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15780 AN: 151994 Hom.: 1059 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.126 AC: 15731 AN: 125090 Hom.: 1236 Cov.: 4 AF XY: 0.125 AC XY: 7568 AN XY: 60512

African (AFR) AF: 0.0394 AC: 201 AN: 5098

American (AMR) AF: 0.184 AC: 924 AN: 5020

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 730 AN: 6198

East Asian (EAS) AF: 0.255 AC: 3229 AN: 12658

South Asian (SAS) AF: 0.195 AC: 607 AN: 3114

European-Finnish (FIN) AF: 0.0834 AC: 302 AN: 3620

Middle Eastern (MID) AF: 0.133 AC: 88 AN: 664

European-Non Finnish (NFE) AF: 0.107 AC: 8507 AN: 79428

Other (OTH) AF: 0.123 AC: 1143 AN: 9290

GnomAD4 genome AF: 0.104 AC: 15792 AN: 152112 Hom.: 1063 Cov.: 32 AF XY: 0.106 AC XY: 7859 AN XY: 74370

African (AFR) AF: 0.0443 AC: 1838 AN: 41506

American (AMR) AF: 0.155 AC: 2364 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 401 AN: 3466

East Asian (EAS) AF: 0.279 AC: 1444 AN: 5168

South Asian (SAS) AF: 0.191 AC: 920 AN: 4810

European-Finnish (FIN) AF: 0.0857 AC: 906 AN: 10574

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7580 AN: 67982

Other (OTH) AF: 0.121 AC: 255 AN: 2114

Alfa AF: 0.102 Hom.: 118

Bravo AF: 0.107

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25814643)

Hereditary spastic paraplegia Benign:1

Nov 18, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spastic paraplegia 45 Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.0
DANN	Benign	0.55
PhyloP100		0.28
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: rs10786736; hg19: chr10-104849116;