chr2-96816435-C-A

Variant names:

• chr2-96816435-C-A
• rs2079317690
• NM_017623.5:c.158C>A

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.158C>A​(p.Ala53Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000802 in 1,246,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A53V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• 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=0.19697565).

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.158C>A	p.Ala53Glu	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.158C>A	p.Ala53Glu	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.158C>A	p.Ala53Glu	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.158C>A	p.Ala53Glu	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.158C>A	p.Ala53Glu	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.02e-7 AC: 1 AN: 1246506 Hom.: 0 Cov.: 31 AF XY: 0.00000164 AC XY: 1 AN XY: 610420

⚠️ 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: 24846

American (AMR) AF: 0.00 AC: 0 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18678

East Asian (EAS) AF: 0.00 AC: 0 AN: 27690

South Asian (SAS) AF: 0.00 AC: 0 AN: 57464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3730

European-Non Finnish (NFE) AF: 9.90e-7 AC: 1 AN: 1010406

Other (OTH) AF: 0.00 AC: 0 AN: 50992

⚠️ 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	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.19
DANN	Benign	0.74
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.25
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.18
Sift	Benign	0.13	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.059
MutPred		0.41		Gain of solvent accessibility (P = 0.005)
MVP		0.055
ClinPred		0.069	T
GERP RS		-0.84
PromoterAI		0.046	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.6
Varity_R		0.098
gMVP		0.50
Mutation Taster		=92/8	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: rs2079317690; hg19: chr2-97482172;