rs3740387

Variant names:

• chr10-103089711-G-A
• rs3740387
• NM_001351169.2:c.1647C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-103089711-G-A
• chr10-103089711-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001351169.2(NT5C2):​c.1647C>T​(p.Asp549Asp) 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:3
• Conservation: PhyloP100: 0.259
• Publications: 43 publications found

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]

CNNM2 Gene-Disease associations (from GenCC):

• hypomagnesemia, seizures, and intellectual disability 1

  Inheritance: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351169.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5C2	NM_001351169.2	MANE Select	c.1647C>T	p.Asp549Asp	synonymous	Exon 19 of 19	NP_001338098.1	P49902-1
	CNNM2	NM_017649.5	MANE Select	c.*12531G>A		3_prime_UTR	Exon 8 of 8	NP_060119.3
	NT5C2	NM_001351170.2		c.1671C>T	p.Asp557Asp	synonymous	Exon 19 of 19	NP_001338099.1	A0A6Q8PHP0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5C2	ENST00000404739.8	TSL:1 MANE Select	c.1647C>T	p.Asp549Asp	synonymous	Exon 19 of 19	ENSP00000383960.3	P49902-1
	NT5C2	ENST00000343289.9	TSL:1	c.1647C>T	p.Asp549Asp	synonymous	Exon 18 of 18	ENSP00000339479.5	P49902-1
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.*12531G>A		3_prime_UTR	Exon 8 of 8	ENSP00000358894.3	Q9H8M5-1

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

GnomAD2 exomes AF: 0.413 AC: 103054 AN: 249798 AF XY: 0.414

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 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

African (AFR) AF: 0.385 AC: 12875 AN: 33412

American (AMR) AF: 0.419 AC: 18638 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 10955 AN: 26018

East Asian (EAS) AF: 0.413 AC: 16380 AN: 39666

South Asian (SAS) AF: 0.438 AC: 37632 AN: 85944

European-Finnish (FIN) AF: 0.366 AC: 19516 AN: 53364

Middle Eastern (MID) AF: 0.438 AC: 2481 AN: 5668

European-Non Finnish (NFE) AF: 0.396 AC: 439524 AN: 1110952

Other (OTH) AF: 0.407 AC: 24540 AN: 60296

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

African (AFR) AF: 0.388 AC: 15991 AN: 41202

American (AMR) AF: 0.403 AC: 6141 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1494 AN: 3464

East Asian (EAS) AF: 0.474 AC: 2445 AN: 5154

South Asian (SAS) AF: 0.426 AC: 2041 AN: 4788

European-Finnish (FIN) AF: 0.365 AC: 3833 AN: 10500

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28184 AN: 67902

Other (OTH) AF: 0.419 AC: 881 AN: 2104

Alfa AF: 0.410 Hom.: 22075

Bravo AF: 0.407

Asia WGS AF: 0.415 AC: 1441 AN: 3478

EpiCase AF: 0.405

EpiControl AF: 0.408

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 45 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.41
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs3740387; hg19: chr10-104849468; COSMIC: COSV58415369; COSMIC: COSV58415369;