2-96816653-G-C

Variant names:

• chr2-96816653-G-C
• rs1036231967
• NM_017623.5:c.376G>C

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.376G>C​(p.Gly126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 926,752 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. 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. G126W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• 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=0.15127435).

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.376G>C	p.Gly126Arg	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.376G>C	p.Gly126Arg	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.376G>C	p.Gly126Arg	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.376G>C	p.Gly126Arg	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.376G>C	p.Gly126Arg	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000432 AC: 4 AN: 926752 Hom.: 0 Cov.: 30 AF XY: 0.00000690 AC XY: 3 AN XY: 434494

African (AFR) AF: 0.00 AC: 0 AN: 18090

American (AMR) AF: 0.00 AC: 0 AN: 3862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8058

East Asian (EAS) AF: 0.00 AC: 0 AN: 10022

South Asian (SAS) AF: 0.00 AC: 0 AN: 18142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2110

European-Non Finnish (NFE) AF: 0.00000486 AC: 4 AN: 823090

Other (OTH) AF: 0.00 AC: 0 AN: 33140

GnomAD4 genome Cov.: 32

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	Benign	0.14
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.0096	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.16
Sift	Benign	0.081	T
Sift4G	Uncertain	0.035	D
Polyphen		0.078	B
Vest4		0.20
MutPred		0.29		Gain of methylation at G126 (P = 0.0131)
MVP		0.20
ClinPred		0.26	T
GERP RS		0.59
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.7
Varity_R		0.095
gMVP		0.36
Mutation Taster		=87/13	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: rs1036231967; hg19: chr2-97482390;