Variant chr2-96761046-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020184.4(CNNM4):c.47G>A(p.Arg16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,233,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

CNNM4
NM_020184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.56

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4053018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM4	NM_020184.4 linkuse as main transcript	c.47G>A	p.Arg16His	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.47G>A	p.Arg16His	missense_variant	1/7	1	NM_020184.4	P1	Q6P4Q7-1

Frequencies

GnomAD3 genomes

AF:

0.0000732

AC:

AN:

150240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000119

Gnomad OTH

AF:

0.000484

GnomAD4 exome

AF:

0.0000406

AC:

AN:

1082800

Hom.:

Cov.:

AF XY:

0.0000450

AC XY:

AN XY:

511664

show subpopulations

Gnomad4 AFR exome

AF:

0.0000442

Gnomad4 AMR exome

AF:

0.000245

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:

0.0000414

Gnomad4 OTH exome

AF:

0.0000462

GnomAD4 genome

AF:

0.0000732

AC:

AN:

150348

Hom.:

Cov.:

AF XY:

0.0000818

AC XY:

AN XY:

73372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000119

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 16 of the CNNM4 protein (p.Arg16His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CNNM4-related conditions. ClinVar contains an entry for this variant (Variation ID: 957264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.030

Eigen

Benign

0.039

Eigen_PC

Benign

-0.0040

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.69

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.83

REVEL

Benign

0.23

Sift

Benign

0.26

Sift4G

Uncertain

0.036

Polyphen

0.92

Vest4

0.23

MutPred

0.41

Loss of methylation at R16 (P = 0.0109);

MVP

0.83

MPC

1.3

ClinPred

0.77

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.32

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