chr2-96816347-G-T

Variant names:

• chr2-96816347-G-T
• rs1309963015
• NM_017623.5:c.70G>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.70G>T​(p.Ala24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000877 in 1,140,144 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. A24T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• 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=0.18238407).

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.70G>T	p.Ala24Ser	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.70G>T	p.Ala24Ser	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.70G>T	p.Ala24Ser	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.70G>T	p.Ala24Ser	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.70G>T	p.Ala24Ser	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.77e-7 AC: 1 AN: 1140144 Hom.: 0 Cov.: 31 AF XY: 0.00000182 AC XY: 1 AN XY: 548004

African (AFR) AF: 0.00 AC: 0 AN: 23290

American (AMR) AF: 0.00 AC: 0 AN: 8918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15108

East Asian (EAS) AF: 0.00 AC: 0 AN: 26922

South Asian (SAS) AF: 0.00 AC: 0 AN: 36910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3164

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 951782

Other (OTH) AF: 0.00 AC: 0 AN: 45636

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.29
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.24	N
REVEL	Benign	0.20
Sift	Benign	0.073	T
Sift4G	Benign	0.70	T
Polyphen		0.76	P
Vest4		0.081
MutPred		0.26		Gain of glycosylation at A24 (P = 0.0042)
MVP		0.21
ClinPred		0.72	D
GERP RS		4.2
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.097
gMVP		0.17
Mutation Taster		=83/17	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: rs1309963015; hg19: chr2-97482084;