10-102918575-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM2 PP2 BP4_Strong BP6_Moderate BS1

The NM_017649.5(CNNM2):c.95G>T(p.Ser32Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000702 in 1,581,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.02

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNNM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.01654169).
• BP6: Variant 10-102918575-G-T is Benign according to our data. Variant chr10-102918575-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2909399.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000679 (97/1428862) while in subpopulation NFE AF= 0.0000291 (32/1099782). AF 95% confidence interval is 0.0000211. There are 0 homozygotes in gnomad4_exome. There are 47 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM2	NM_017649.5	c.95G>T	p.Ser32Ile	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3	c.95G>T	p.Ser32Ile	missense_variant	1/7
CNNM2	NM_199077.3	c.95G>T	p.Ser32Ile	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.95G>T	p.Ser32Ile	missense_variant	1/8	1	NM_017649.5	P4
CNNM2	ENST00000369875.3	c.95G>T	p.Ser32Ile	missense_variant	1/2	1
CNNM2	ENST00000433628.2	c.95G>T	p.Ser32Ile	missense_variant	1/7	2		A1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152180 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000144 AC: 27 AN: 187004 Hom.: 0 AF XY: 0.000163 AC XY: 17 AN XY: 104310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000704

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00155

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000679 AC: 97 AN: 1428862 Hom.: 0 Cov.: 32 AF XY: 0.0000663 AC XY: 47 AN XY: 709248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.0000291

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000602 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0063	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.019	T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.77	N;N;N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.037	B;.;B
Vest4		0.17
MutPred		0.31		Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);
MVP		0.043
ClinPred		0.25	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs749255923; hg19: chr10-104678332;