Genetic Variant CNNM1:p.Pro120Arg (chr10-99329746-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020348.3(CNNM1):c.359C>G(p.Pro120Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000016 in 1,502,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P120H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CNNM1
NM_020348.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.14

Publications

0 publications found

Variant links:

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]

CNNM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24229664).

BS2

High AC in GnomAdExome4 at 22 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNNM1	NM_020348.3	MANE Select	c.359C>G	p.Pro120Arg	missense	Exon 1 of 11	NP_065081.2	Q9NRU3-1
CNNM1	NM_001345887.2		c.359C>G	p.Pro120Arg	missense	Exon 1 of 12	NP_001332816.1	A0A8Q3SIV9
CNNM1	NM_001345889.2		c.359C>G	p.Pro120Arg	missense	Exon 1 of 11	NP_001332818.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNNM1	ENST00000356713.5	TSL:1 MANE Select	c.359C>G	p.Pro120Arg	missense	Exon 1 of 11	ENSP00000349147.4	Q9NRU3-1
CNNM1	ENST00000696687.1		c.359C>G	p.Pro120Arg	missense	Exon 1 of 12	ENSP00000512809.1	A0A8Q3SIV9
CNNM1	ENST00000914274.1		c.359C>G	p.Pro120Arg	missense	Exon 1 of 10	ENSP00000584333.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151726

Hom.:

Cov.:

show subpopulations

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

98180

AF XY:

0.0000360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000519

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000163

AC:

AN:

1350974

Hom.:

Cov.:

AF XY:

0.0000225

AC XY:

AN XY:

666598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27538

American (AMR)

AF:

0.00

AC:

AN:

31388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23310

East Asian (EAS)

AF:

0.00

AC:

AN:

32074

South Asian (SAS)

AF:

0.00

AC:

AN:

75088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.0000206

AC:

AN:

1067362

Other (OTH)

AF:

0.00

AC:

AN:

56256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41294

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67870

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0029

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.0

PhyloP100

4.1

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.18

REVEL

Uncertain

0.33

Sift

Benign

0.47

Sift4G

Benign

0.39

Polyphen

0.81

Vest4

0.18

MutPred

0.13

Gain of catalytic residue at P120 (P = 0.0566)

MVP

0.13

ClinPred

0.15

GERP RS

3.7

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.17

gMVP

0.27

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over