chr10-103089678-T-TTCCTCCTCC

Variant names:

• chr10-103089678-T-TTCCTCCTCC
• rs537259520
• NM_001351169.2:c.1671_1679dupGGAGGAGGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001351169.2(NT5C2):​c.1671_1679dupGGAGGAGGA​(p.Glu558_Glu560dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,876 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NT5C2 NM_001351169.2 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 1 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001351169.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NT5C2	NM_001351169.2	c.1671_1679dupGGAGGAGGA	p.Glu558_Glu560dup	disruptive_inframe_insertion	Exon 19 of 19	ENST00000404739.8	NP_001338098.1
CNNM2	NM_017649.5	c.*12507_*12515dupCTCCTCCTC		3_prime_UTR_variant	Exon 8 of 8	ENST00000369878.9	NP_060119.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NT5C2	ENST00000404739.8	c.1671_1679dupGGAGGAGGA	p.Glu558_Glu560dup	disruptive_inframe_insertion	Exon 19 of 19	1	NM_001351169.2	ENSP00000383960.3
CNNM2	ENST00000369878.9	c.*12507_*12515dupCTCCTCCTC		3_prime_UTR_variant	Exon 8 of 8	1	NM_017649.5	ENSP00000358894.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000453 AC: 1 AN: 220626 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000986

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407876 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 699662

African (AFR) AF: 0.00 AC: 0 AN: 32108

American (AMR) AF: 0.00 AC: 0 AN: 42314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24462

East Asian (EAS) AF: 0.00 AC: 0 AN: 38856

South Asian (SAS) AF: 0.00 AC: 0 AN: 80968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1073670

Other (OTH) AF: 0.00 AC: 0 AN: 58154

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=74/26	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs537259520; hg19: chr10-104849435;