Genetic Variant CNNM1:p.Pro148Thr (chr10-99329829-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020348.3(CNNM1):c.442C>A(p.Pro148Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,277,432 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. 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. P148S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

CNNM1
NM_020348.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.616

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:

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ACMG classification

Classification was made for transcript

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=0.09814346).

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.442C>A	p.Pro148Thr	missense	Exon 1 of 11	NP_065081.2	Q9NRU3-1
CNNM1	NM_001345887.2		c.442C>A	p.Pro148Thr	missense	Exon 1 of 12	NP_001332816.1	A0A8Q3SIV9
CNNM1	NM_001345889.2		c.442C>A	p.Pro148Thr	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.442C>A	p.Pro148Thr	missense	Exon 1 of 11	ENSP00000349147.4	Q9NRU3-1
CNNM1	ENST00000696687.1		c.442C>A	p.Pro148Thr	missense	Exon 1 of 12	ENSP00000512809.1	A0A8Q3SIV9
CNNM1	ENST00000914274.1		c.442C>A	p.Pro148Thr	missense	Exon 1 of 10	ENSP00000584333.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000157

AC:

AN:

1277432

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

622790

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25240

American (AMR)

AF:

0.00

AC:

AN:

19160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19234

East Asian (EAS)

AF:

0.00

AC:

AN:

28906

South Asian (SAS)

AF:

0.0000159

AC:

AN:

63030

European-Finnish (FIN)

AF:

0.0000279

AC:

AN:

35854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3882

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1029224

Other (OTH)

AF:

0.00

AC:

AN:

52902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0067

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.34

PhyloP100

0.62

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.29

REVEL

Benign

0.17

Sift

Uncertain

0.028

Sift4G

Benign

0.56

Polyphen

0.012

Vest4

0.040

MutPred

0.14

Gain of phosphorylation at P148 (P = 0.0668)

MVP

0.068

ClinPred

0.18

GERP RS

2.9

PromoterAI

0.0080

Neutral

(source)

Varity_R

0.16

gMVP

0.45

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over