NM_020348.3:c.494G>C

Variant names:

• chr10-99329881-G-C
• rs1358897676
• NM_020348.3:c.494G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_020348.3(CNNM1):​c.494G>C​(p.Arg165Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,394,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: CNNM1 NM_020348.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

Genes affected

CNNM1 (HGNC:102): (cyclin and CBS domain divalent metal cation transport mediator 1) This gene encodes a member of the ancient conserved domain protein family. The encoded protein may bind copper. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35267687).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020348.3. 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
	CNNM1	NM_020348.3	MANE Select	c.494G>C	p.Arg165Pro	missense	Exon 1 of 11	NP_065081.2	Q9NRU3-1
	CNNM1	NM_001345887.2		c.494G>C	p.Arg165Pro	missense	Exon 1 of 12	NP_001332816.1	A0A8Q3SIV9
	CNNM1	NM_001345889.2		c.494G>C	p.Arg165Pro	missense	Exon 1 of 11	NP_001332818.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM1	ENST00000356713.5	TSL:1 MANE Select	c.494G>C	p.Arg165Pro	missense	Exon 1 of 11	ENSP00000349147.4	Q9NRU3-1
	CNNM1	ENST00000696687.1		c.494G>C	p.Arg165Pro	missense	Exon 1 of 12	ENSP00000512809.1	A0A8Q3SIV9
	CNNM1	ENST00000914274.1		c.494G>C	p.Arg165Pro	missense	Exon 1 of 10	ENSP00000584333.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00000966 AC: 12 AN: 1241990 Hom.: 0 Cov.: 29 AF XY: 0.00000497 AC XY: 3 AN XY: 603222

African (AFR) AF: 0.00 AC: 0 AN: 24024

American (AMR) AF: 0.00 AC: 0 AN: 11932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17282

East Asian (EAS) AF: 0.00 AC: 0 AN: 28270

South Asian (SAS) AF: 0.00 AC: 0 AN: 56192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.0000118 AC: 12 AN: 1013510

Other (OTH) AF: 0.00 AC: 0 AN: 51086

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0032	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.17
MutPred		0.38		Loss of MoRF binding (P = 6e-04)
MVP		0.48
ClinPred		0.84	D
GERP RS		3.6
Varity_R		0.60
gMVP		0.84
Mutation Taster		=62/38	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: rs1358897676; hg19: chr10-101089638;