rs1375543379

Variant names:

• chr2-96816714-C-T
• rs1375543379
• NM_017623.5:c.437C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017623.5(CNNM3):​c.437C>T​(p.Ala146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 864,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.707
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25245762).

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.437C>T	p.Ala146Val	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.437C>T	p.Ala146Val	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.437C>T	p.Ala146Val	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.437C>T	p.Ala146Val	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.437C>T	p.Ala146Val	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000104 AC: 9 AN: 864700 Hom.: 0 Cov.: 30 AF XY: 0.00000745 AC XY: 3 AN XY: 402680

African (AFR) AF: 0.00 AC: 0 AN: 16310

American (AMR) AF: 0.00 AC: 0 AN: 2102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5860

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 17596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1768

European-Non Finnish (NFE) AF: 0.0000115 AC: 9 AN: 783242

Other (OTH) AF: 0.00 AC: 0 AN: 29132

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.096
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.38	N
PhyloP100		-0.71
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.18
Sift	Benign	0.65	T
Sift4G	Benign	0.45	T
Polyphen		0.13	B
Vest4		0.12
MutPred		0.58		Loss of disorder (P = 0.0441)
MVP		0.12
ClinPred		0.15	T
GERP RS		1.7
PromoterAI		-0.033	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Varity_R		0.049
gMVP		0.40
Mutation Taster		=85/15	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: rs1375543379; hg19: chr2-97482451;