10-103089678-TTCCTCC-TTCC

Variant names:

• chr10-103089678-TTCC-T
• rs537259520
• NM_001351169.2:c.1677_1679delGGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_001351169.2(NT5C2):​c.1677_1679delGGA​(p.Glu560del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,539,214 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E559E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: NT5C2 NM_001351169.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001351169.2
• BP6: Variant 10-103089678-TTCC-T is Benign according to our data. Variant chr10-103089678-TTCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1025816.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000204 (31/152140) while in subpopulation AFR AF = 0.000385 (16/41530). AF 95% confidence interval is 0.000241. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1677_1679delGGA	p.Glu560del	disruptive_inframe_deletion	Exon 19 of 19	NP_001338098.1	P49902-1
	CNNM2	NM_017649.5	MANE Select	c.*12513_*12515delCTC		3_prime_UTR	Exon 8 of 8	NP_060119.3
	NT5C2	NM_001351170.2		c.1701_1703delGGA	p.Glu568del	disruptive_inframe_deletion	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.1677_1679delGGA	p.Glu560del	disruptive_inframe_deletion	Exon 19 of 19	ENSP00000383960.3	P49902-1
	NT5C2	ENST00000343289.9	TSL:1	c.1677_1679delGGA	p.Glu560del	disruptive_inframe_deletion	Exon 18 of 18	ENSP00000339479.5	P49902-1
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.*12513_*12515delCTC		3_prime_UTR	Exon 8 of 8	ENSP00000358894.3	Q9H8M5-1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000503 AC: 111 AN: 220626 AF XY: 0.000532

Gnomad AFR exome AF: 0.000723

Gnomad AMR exome AF: 0.000374

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.000302

Gnomad FIN exome AF: 0.000199

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.000953

GnomAD4 exome AF: 0.000229 AC: 317 AN: 1387074 Hom.: 1 AF XY: 0.000266 AC XY: 183 AN XY: 689210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000790 AC: 25 AN: 31632

American (AMR) AF: 0.000265 AC: 11 AN: 41586

Ashkenazi Jewish (ASJ) AF: 0.000166 AC: 4 AN: 24034

East Asian (EAS) AF: 0.000156 AC: 6 AN: 38382

South Asian (SAS) AF: 0.000417 AC: 33 AN: 79224

European-Finnish (FIN) AF: 0.000156 AC: 8 AN: 51424

Middle Eastern (MID) AF: 0.000376 AC: 2 AN: 5324

European-Non Finnish (NFE) AF: 0.000202 AC: 214 AN: 1058192

Other (OTH) AF: 0.000244 AC: 14 AN: 57276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74382

African (AFR) AF: 0.000385 AC: 16 AN: 41530

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00458 Hom.: 0

Bravo AF: 0.000280

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 45 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=70/30	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: rs537259520; hg19: chr10-104849435; COSMIC: COSV58414583; COSMIC: COSV58414583;