2-96816701-G-C

Variant names:

• chr2-96816701-G-C
• rs1409682427
• NM_017623.5:c.424G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017623.5(CNNM3):​c.424G>C​(p.Ala142Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 147,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A142T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• 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]

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37191564).

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.424G>C	p.Ala142Pro	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.424G>C	p.Ala142Pro	missense	Exon 1 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.424G>C	p.Ala142Pro	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.424G>C	p.Ala142Pro	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.424G>C	p.Ala142Pro	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.00000679 AC: 1 AN: 147202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 866740 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 403808

African (AFR) AF: 0.00 AC: 0 AN: 16350

American (AMR) AF: 0.00 AC: 0 AN: 2192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5894

East Asian (EAS) AF: 0.00 AC: 0 AN: 4992

South Asian (SAS) AF: 0.00 AC: 0 AN: 17622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1776

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 784578

Other (OTH) AF: 0.00 AC: 0 AN: 29266

GnomAD4 genome AF: 0.00000679 AC: 1 AN: 147202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71614

African (AFR) AF: 0.0000244 AC: 1 AN: 40948

American (AMR) AF: 0.00 AC: 0 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66104

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.042	D
Sift4G	Benign	0.086	T
Polyphen		0.98	D
Vest4		0.32
MutPred		0.70		Loss of helix (P = 0.0076)
MVP		0.14
ClinPred		0.71	D
GERP RS		0.50
PromoterAI		-0.043	Neutral
Varity_R		0.61
gMVP		0.76
Mutation Taster		=83/17	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: rs1409682427; hg19: chr2-97482438;