NM_001351169.2:c.1662A>G

Variant names:

• chr10-103089696-T-C
• rs116702241
• NM_001351169.2:c.1662A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001351169.2(NT5C2):​c.1662A>G​(p.Glu554Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,609,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: NT5C2 NM_001351169.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.343
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-103089696-T-C is Benign according to our data. Variant chr10-103089696-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 474943.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.343 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NT5C2	NM_001351169.2	c.1662A>G	p.Glu554Glu	synonymous_variant	Exon 19 of 19	ENST00000404739.8	NP_001338098.1
CNNM2	NM_017649.5	c.*12516T>C		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.1662A>G	p.Glu554Glu	synonymous_variant	Exon 19 of 19	1	NM_001351169.2	ENSP00000383960.3
CNNM2	ENST00000369878.9	c.*12516T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_017649.5	ENSP00000358894.3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000418 AC: 103 AN: 246642 AF XY: 0.000368

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1457540 Hom.: 0 Cov.: 30 AF XY: 0.000199 AC XY: 144 AN XY: 724848

African (AFR) AF: 0.0000300 AC: 1 AN: 33340

American (AMR) AF: 0.0000226 AC: 1 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.0000774 AC: 2 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 85532

European-Finnish (FIN) AF: 0.00327 AC: 174 AN: 53250

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5636

European-Non Finnish (NFE) AF: 0.0000766 AC: 85 AN: 1109816

Other (OTH) AF: 0.000465 AC: 28 AN: 60196

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 45 Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.58
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

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: rs116702241; hg19: chr10-104849453;