Variant 2-96761039-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020184.4(CNNM4):c.40C>G(p.Pro14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,224,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00010 ( 1 hom., cov: 31)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Consequence

CNNM4
NM_020184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.820

Variant links:

Genes affected

CNNM4 (HGNC:105): (cyclin and CBS domain divalent metal cation transport mediator 4) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]

CNNM4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18040109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM4	NM_020184.4 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/7	ENST00000377075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM4	ENST00000377075.3 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/7	1	NM_020184.4	P1	Q6P4Q7-1

Frequencies

GnomAD3 genomes

AF:

0.000100

AC:

AN:

149968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000364

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.31e-7

AC:

AN:

1074606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

507624

show subpopulations

Gnomad4 AFR exome

AF:

0.0000448

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000100

AC:

AN:

149968

Hom.:

Cov.:

AF XY:

0.0000684

AC XY:

AN XY:

73104

show subpopulations

Gnomad4 AFR

AF:

0.000364

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.40C>G (p.P14A) alteration is located in exon 1 (coding exon 1) of the CNNM4 gene. This alteration results from a C to G substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by an alanine (A). 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

0.056

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.024

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.25

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.18

REVEL

Benign

0.15

Sift

Benign

0.35

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.15

MutPred

0.20

Gain of helix (P = 0.005);

MVP

0.66

MPC

1.0

ClinPred

0.30

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.034

gMVP

0.29

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