chr10-99330198-C-A

Variant names:

• chr10-99330198-C-A
• rs931737637
• NM_020348.3:c.811C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020348.3(CNNM1):​c.811C>A​(p.Arg271Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,358,396 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CNNM1 NM_020348.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3723746).

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.811C>A	p.Arg271Ser	missense	Exon 1 of 11	NP_065081.2	Q9NRU3-1
	CNNM1	NM_001345887.2		c.811C>A	p.Arg271Ser	missense	Exon 1 of 12	NP_001332816.1	A0A8Q3SIV9
	CNNM1	NM_001345889.2		c.811C>A	p.Arg271Ser	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.811C>A	p.Arg271Ser	missense	Exon 1 of 11	ENSP00000349147.4	Q9NRU3-1
	CNNM1	ENST00000696687.1		c.811C>A	p.Arg271Ser	missense	Exon 1 of 12	ENSP00000512809.1	A0A8Q3SIV9
	CNNM1	ENST00000914274.1		c.811C>A	p.Arg271Ser	missense	Exon 1 of 10	ENSP00000584333.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1358396 Hom.: 0 Cov.: 29 AF XY: 0.00000150 AC XY: 1 AN XY: 667502

African (AFR) AF: 0.00 AC: 0 AN: 30754

American (AMR) AF: 0.00 AC: 0 AN: 31912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22508

East Asian (EAS) AF: 0.00 AC: 0 AN: 35452

South Asian (SAS) AF: 0.00 AC: 0 AN: 72702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1066218

Other (OTH) AF: 0.00 AC: 0 AN: 56590

GnomAD4 genome Cov.: 33

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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.013	D
Sift4G	Benign	0.14	T
Polyphen		0.95	P
Vest4		0.28
MutPred		0.60		Loss of MoRF binding (P = 0.0345)
MVP		0.28
ClinPred		0.85	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.66
Mutation Taster		=43/57	disease causing

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: rs931737637; hg19: chr10-101089955;