2-96826967-C-T

Variant names:

• chr2-96826967-C-T
• rs948665847
• NM_017623.5:c.1504C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_017623.5(CNNM3):​c.1504C>T​(p.Arg502Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41
• Publications: 0 publications found

Genes affected

CNNM3 (HGNC:104): (cyclin and CBS domain divalent metal cation transport mediator 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in ion transport; magnesium ion homeostasis; and transmembrane transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD23 (HGNC:24470): (ankyrin repeat domain 23) This gene is a member of the muscle ankyrin repeat protein (MARP) family and encodes a protein with four tandem ankyrin-like repeats. The protein is localized to the nucleus, functioning as a transcriptional regulator. Expression of this protein is induced during recovery following starvation. [provided by RefSeq, Jul 2008]

CNNM3-DT (HGNC:53592): (CNNM3 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017623.5. 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
	CNNM3	NM_017623.5	MANE Select	c.1504C>T	p.Arg502Cys	missense	Exon 3 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.1360C>T	p.Arg454Cys	missense	Exon 2 of 7	NP_951060.1	Q8NE01-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM3	ENST00000305510.4	TSL:1 MANE Select	c.1504C>T	p.Arg502Cys	missense	Exon 3 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000465224.5	TSL:1	n.162C>T		non_coding_transcript_exon	Exon 2 of 4
	CNNM3	ENST00000947263.1		c.1504C>T	p.Arg502Cys	missense	Exon 3 of 8	ENSP00000617322.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251234 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727140

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00144 AC: 22 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.56		Loss of loop (P = 0.0512)
MVP		0.79
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.72
Mutation Taster		=35/65	disease causing

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: rs948665847; hg19: chr2-97492704;