10-103089711-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001351169.2(NT5C2):c.1647C>T(p.Asp549=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,611,386 control chromosomes in the GnomAD database, including 129,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12616 hom., cov: 30)
  • Exomes 𝑓: 0.40 (117069 hom.)
• Consequence: NT5C2 NM_001351169.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.259

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-103089711-G-A is Benign according to our data. Variant chr10-103089711-G-A is described in ClinVar as [Benign]. Clinvar id is 380852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.259 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NT5C2	NM_001351169.2	c.1647C>T	p.Asp549=	synonymous_variant	19/19	ENST00000404739.8
CNNM2	NM_017649.5	c.*12531G>A		3_prime_UTR_variant	8/8	ENST00000369878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NT5C2	ENST00000404739.8	c.1647C>T	p.Asp549=	synonymous_variant	19/19	1	NM_001351169.2	P1
CNNM2	ENST00000369878.9	c.*12531G>A		3_prime_UTR_variant	8/8	1	NM_017649.5	P4

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61405 AN: 151448 Hom.: 12605 Cov.: 30

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.413 AC: 103054 AN: 249798 Hom.: 21314 AF XY: 0.414 AC XY: 55862 AN XY: 135000

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.414

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.475

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.399 AC: 582541 AN: 1459820 Hom.: 117069 Cov.: 37 AF XY: 0.400 AC XY: 290702 AN XY: 726162

Gnomad4 AFR exome AF: 0.385

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.413

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.405 AC: 61457 AN: 151566 Hom.: 12616 Cov.: 30 AF XY: 0.403 AC XY: 29827 AN XY: 74032

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.365

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.419

Alfa AF: 0.410 Hom.: 16583

Bravo AF: 0.407

Asia WGS AF: 0.415 AC: 1441 AN: 3478

EpiCase AF: 0.405

EpiControl AF: 0.408

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	11
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3740387; hg19: chr10-104849468; COSMIC: COSV58415369; COSMIC: COSV58415369;