chr2-96816312-G-C

Variant names:

• chr2-96816312-G-C
• NM_017623.5:c.35G>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.35G>C​(p.Gly12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000878 in 1,139,488 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: 8.8e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0880
• 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=0.1535053).

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.35G>C	p.Gly12Ala	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.35G>C	p.Gly12Ala	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.35G>C	p.Gly12Ala	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.35G>C	p.Gly12Ala	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.35G>C	p.Gly12Ala	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.78e-7 AC: 1 AN: 1139488 Hom.: 0 Cov.: 31 AF XY: 0.00000183 AC XY: 1 AN XY: 547746

African (AFR) AF: 0.00 AC: 0 AN: 23500

American (AMR) AF: 0.00 AC: 0 AN: 10132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15066

East Asian (EAS) AF: 0.00 AC: 0 AN: 27186

South Asian (SAS) AF: 0.0000282 AC: 1 AN: 35400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3084

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 953154

Other (OTH) AF: 0.00 AC: 0 AN: 45622

GnomAD4 genome Cov.: 32

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	0.11
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.088
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.21	N
REVEL	Benign	0.14
Sift	Benign	0.53	T
Sift4G	Benign	1.0	T
Polyphen		0.22	B
Vest4		0.12
MutPred		0.28		Gain of helix (P = 0.0861)
MVP		0.15
ClinPred		0.18	T
GERP RS		4.1
PromoterAI		-0.032	Neutral
Varity_R		0.078
gMVP		0.32
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr2-97482049;