2-96817014-G-C

Variant names:

• chr2-96817014-G-C
• rs1311694187
• NM_017623.5:c.737G>C

Variant summary

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

The NM_017623.5(CNNM3):​c.737G>C​(p.Arg246Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000821 in 1,218,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R246L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.498
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.737G>C	p.Arg246Pro	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.737G>C	p.Arg246Pro	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.737G>C	p.Arg246Pro	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.737G>C	p.Arg246Pro	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.737G>C	p.Arg246Pro	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.21e-7 AC: 1 AN: 1218590 Hom.: 0 Cov.: 31 AF XY: 0.00000167 AC XY: 1 AN XY: 600588

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23732

American (AMR) AF: 0.00 AC: 0 AN: 18982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19116

East Asian (EAS) AF: 0.00 AC: 0 AN: 22824

South Asian (SAS) AF: 0.00 AC: 0 AN: 65206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3366

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 988458

Other (OTH) AF: 0.00 AC: 0 AN: 47774

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.50
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.73		Loss of MoRF binding (P = 0.0097)
MVP		0.44
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.92
gMVP		0.84
Mutation Taster		=76/24	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: rs1311694187; hg19: chr2-97482751;