chr2-96816660-C-T

Variant names:

• chr2-96816660-C-T
• rs561303055
• NM_017623.5:c.383C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017623.5(CNNM3):​c.383C>T​(p.Ala128Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,054,906 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: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047954172).

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.383C>T	p.Ala128Val	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.383C>T	p.Ala128Val	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.383C>T	p.Ala128Val	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.383C>T	p.Ala128Val	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.383C>T	p.Ala128Val	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.000462 AC: 68 AN: 147298 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000408 AC: 37 AN: 907500 Hom.: 0 Cov.: 30 AF XY: 0.0000306 AC XY: 13 AN XY: 424838

African (AFR) AF: 0.00207 AC: 36 AN: 17376

American (AMR) AF: 0.000300 AC: 1 AN: 3338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7338

East Asian (EAS) AF: 0.00 AC: 0 AN: 8142

South Asian (SAS) AF: 0.00 AC: 0 AN: 17988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 810906

Other (OTH) AF: 0.00 AC: 0 AN: 31926

GnomAD4 genome AF: 0.000468 AC: 69 AN: 147406 Hom.: 0 Cov.: 32 AF XY: 0.000460 AC XY: 33 AN XY: 71812

African (AFR) AF: 0.00161 AC: 66 AN: 40870

American (AMR) AF: 0.000202 AC: 3 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66196

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.000427 Hom.: 0

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	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.14	N
REVEL	Benign	0.12
Sift	Benign	0.66	T
Sift4G	Benign	0.38	T
Polyphen		0.0050	B
Vest4		0.081
MutPred		0.23		Loss of helix (P = 0.0376)
MVP		0.061
ClinPred		0.072	T
GERP RS		0.20
PromoterAI		-0.041	Neutral
Varity_R		0.059
gMVP		0.32
Mutation Taster		=96/4	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: rs561303055; hg19: chr2-97482397;