10-103089359-G-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.*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:3
• Conservation: PhyloP100: 0.275

Genes affected

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]

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=-0.79).
• BP6: Variant 10-103089359-G-C is Benign according to our data. Variant chr10-103089359-G-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NT5C2	NM_001351169.2	c.*313C>G		3_prime_UTR_variant	19/19	ENST00000404739.8
CNNM2	NM_017649.5	c.*12179G>C		3_prime_UTR_variant	8/8	ENST00000369878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.*12179G>C		3_prime_UTR_variant	8/8	1	NM_017649.5	P4
NT5C2	ENST00000404739.8	c.*313C>G		3_prime_UTR_variant	19/19	1	NM_001351169.2	P1

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

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.123

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

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.0857

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.121

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 18, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

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

Hereditary spastic paraplegia 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.0
Dann	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs10786736; hg19: chr10-104849116;