Genetic Variant CNNM1:p.Pro35Ser (chr10-99329490-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020348.3(CNNM1):c.103C>T(p.Pro35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,496,668 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

CNNM1
NM_020348.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042649478).

BS2

High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM1	NM_020348.3 link	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 11	ENST00000356713.5	NP_065081.2	Q9NRU3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM1	ENST00000356713.5 link	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 11	1	NM_020348.3	ENSP00000349147.4		Q9NRU3-1
CNNM1	ENST00000696687.1 link	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 12			ENSP00000512809.1		A0A8Q3SIV9

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000614

AC:

AN:

104182

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

57926

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000888

Gnomad ASJ exome

AF:

0.000284

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.000824

Gnomad OTH exome

AF:

0.000644

GnomAD4 exome

AF:

0.00114

AC:

1531

AN:

1344342

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

725

AN XY:

663466

show subpopulations

Gnomad4 AFR exome

AF:

0.0000722

Gnomad4 AMR exome

AF:

0.000840

Gnomad4 ASJ exome

AF:

0.0000833

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000799

Gnomad4 FIN exome

AF:

0.000736

Gnomad4 NFE exome

AF:

0.00135

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000604

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000979

Hom.:

Bravo

AF:

0.000733

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000234

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103C>T (p.P35S) alteration is located in exon 1 (coding exon 1) of the CNNM1 gene. This alteration results from a C to T substitution at nucleotide position 103, causing the proline (P) at amino acid position 35 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0019

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.35

REVEL

Benign

0.26

Sift

Benign

0.25

Sift4G

Benign

0.31

Polyphen

0.82

Vest4

0.21

MVP

0.29

ClinPred

0.10

GERP RS

3.8

Varity_R

0.091

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over