2-96761046-G-A

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

2
3
14

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]

Genome browser will be placed here

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
CNNM4NM_020184.4 linkuse as main transcriptc.47G>A p.Arg16His missense_variant 1/7 ENST00000377075.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM4ENST00000377075.3 linkuse as main transcriptc.47G>A p.Arg16His missense_variant 1/71 NM_020184.4 P1Q6P4Q7-1

Frequencies

GnomAD3 genomes
AF:
0.0000732
AC:
11
AN:
150240
Hom.:
0
Cov.:
32
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:
44
AN:
1082800
Hom.:
0
Cov.:
31
AF XY:
0.0000450
AC XY:
23
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:
11
AN:
150348
Hom.:
0
Cov.:
32
AF XY:
0.0000818
AC XY:
6
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.:
0
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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 13, 2022This 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
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.030
T
Eigen
Benign
0.039
Eigen_PC
Benign
-0.0040
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.53
T
M_CAP
Pathogenic
0.90
D
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
0.69
N
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-0.83
N
REVEL
Benign
0.23
Sift
Benign
0.26
T
Sift4G
Uncertain
0.036
D
Polyphen
0.92
P
Vest4
0.23
MutPred
0.41
Loss of methylation at R16 (P = 0.0109);
MVP
0.83
MPC
1.3
ClinPred
0.77
D
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.

Other links and lift over

dbSNP: rs1366713398; hg19: chr2-97426783; API