2-96816438-C-T

Variant names:

• chr2-96816438-C-T
• rs1466477968
• NM_017623.5:c.161C>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.161C>T​(p.Ala54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,415,214 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• 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=0.11060274).

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.161C>T	p.Ala54Val	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.161C>T	p.Ala54Val	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.161C>T	p.Ala54Val	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.161C>T	p.Ala54Val	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.161C>T	p.Ala54Val	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1263160 Hom.: 0 Cov.: 31 AF XY: 0.00000323 AC XY: 2 AN XY: 619298

African (AFR) AF: 0.00 AC: 0 AN: 25472

American (AMR) AF: 0.00 AC: 0 AN: 18578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19726

East Asian (EAS) AF: 0.00 AC: 0 AN: 27742

South Asian (SAS) AF: 0.00 AC: 0 AN: 60806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3852

European-Non Finnish (NFE) AF: 0.00000197 AC: 2 AN: 1016456

Other (OTH) AF: 0.00 AC: 0 AN: 51750

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.70
DANN	Benign	0.80
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-1.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	1.4	N
REVEL	Benign	0.099
Sift	Benign	0.75	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.045
MutPred		0.28		Gain of sheet (P = 0.0266)
MVP		0.055
ClinPred		0.033	T
GERP RS		-1.3
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.7
Varity_R		0.027
gMVP		0.12
Mutation Taster		=97/3	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: rs1466477968; hg19: chr2-97482175;