10-103089387-A-C

Variant names:

• chr10-103089387-A-C
• rs12573221
• NM_017649.5:c.*12207A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017649.5(CNNM2):​c.*12207A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 310,428 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (78 hom., cov: 32)
  • Exomes 𝑓: 0.022 (72 hom.)
• Consequence: CNNM2 NM_017649.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.198
• Publications: 9 publications found

Genes affected

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]

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]

NT5C2 Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 45

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-103089387-A-C is Benign according to our data. Variant chr10-103089387-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1178021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017649.5. 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
	CNNM2	NM_017649.5	MANE Select	c.*12207A>C		3_prime_UTR	Exon 8 of 8	NP_060119.3
	NT5C2	NM_001351169.2	MANE Select	c.*285T>G		3_prime_UTR	Exon 19 of 19	NP_001338098.1	P49902-1
	CNNM2	NM_199076.3		c.*12207A>C		3_prime_UTR	Exon 7 of 7	NP_951058.1	Q9H8M5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.*12207A>C		3_prime_UTR	Exon 8 of 8	ENSP00000358894.3	Q9H8M5-1
	NT5C2	ENST00000404739.8	TSL:1 MANE Select	c.*285T>G		3_prime_UTR	Exon 19 of 19	ENSP00000383960.3	P49902-1
	NT5C2	ENST00000343289.9	TSL:1	c.*285T>G		3_prime_UTR	Exon 18 of 18	ENSP00000339479.5	P49902-1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3442 AN: 152152 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0224 AC: 3547 AN: 158158 Hom.: 72 Cov.: 4 AF XY: 0.0227 AC XY: 1771 AN XY: 77910

African (AFR) AF: 0.0262 AC: 155 AN: 5924

American (AMR) AF: 0.00925 AC: 54 AN: 5838

Ashkenazi Jewish (ASJ) AF: 0.0391 AC: 277 AN: 7086

East Asian (EAS) AF: 0.0424 AC: 631 AN: 14878

South Asian (SAS) AF: 0.104 AC: 393 AN: 3780

European-Finnish (FIN) AF: 0.00918 AC: 65 AN: 7078

Middle Eastern (MID) AF: 0.0484 AC: 39 AN: 806

European-Non Finnish (NFE) AF: 0.0168 AC: 1711 AN: 101598

Other (OTH) AF: 0.0199 AC: 222 AN: 11170

GnomAD4 genome AF: 0.0226 AC: 3435 AN: 152270 Hom.: 78 Cov.: 32 AF XY: 0.0233 AC XY: 1738 AN XY: 74450

African (AFR) AF: 0.0250 AC: 1037 AN: 41554

American (AMR) AF: 0.0105 AC: 160 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 155 AN: 3472

East Asian (EAS) AF: 0.0519 AC: 269 AN: 5180

South Asian (SAS) AF: 0.110 AC: 531 AN: 4814

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1157 AN: 68022

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0195 Hom.: 25

Bravo AF: 0.0209

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.72
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12573221; hg19: chr10-104849144;