2-96761090-T-C

Variant summary

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

The NM_020184.4(CNNM4):ā€‹c.91T>Cā€‹(p.Trp31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,515,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00016 ( 0 hom., cov: 31)
Exomes š‘“: 0.00023 ( 0 hom. )

Consequence

CNNM4
NM_020184.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.805
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13569617).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNNM4NM_020184.4 linkuse as main transcriptc.91T>C p.Trp31Arg missense_variant 1/7 ENST00000377075.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM4ENST00000377075.3 linkuse as main transcriptc.91T>C p.Trp31Arg missense_variant 1/71 NM_020184.4 P1Q6P4Q7-1

Frequencies

GnomAD3 genomes
AF:
0.000159
AC:
24
AN:
150760
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000730
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:
0.000311
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000147
AC:
26
AN:
177062
Hom.:
0
AF XY:
0.000125
AC XY:
12
AN XY:
95794
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000619
Gnomad NFE exome
AF:
0.000310
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000231
AC:
315
AN:
1364790
Hom.:
0
Cov.:
31
AF XY:
0.000229
AC XY:
153
AN XY:
668562
show subpopulations
Gnomad4 AFR exome
AF:
0.0000322
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000277
Gnomad4 FIN exome
AF:
0.0000415
Gnomad4 NFE exome
AF:
0.000285
Gnomad4 OTH exome
AF:
0.000143
GnomAD4 genome
AF:
0.000159
AC:
24
AN:
150760
Hom.:
0
Cov.:
31
AF XY:
0.000122
AC XY:
9
AN XY:
73608
show subpopulations
Gnomad4 AFR
AF:
0.0000730
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:
0.000311
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000182
Hom.:
0
Bravo
AF:
0.000136
ExAC
AF:
0.000217
AC:
26

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 17, 2022This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 31 of the CNNM4 protein (p.Trp31Arg). This variant is present in population databases (rs760633483, gnomAD 0.03%). 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: 288785). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 12, 2016- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 11, 2021The c.91T>C (p.W31R) alteration is located in exon 1 (coding exon 1) of the CNNM4 gene. This alteration results from a T to C substitution at nucleotide position 91, causing the tryptophan (W) at amino acid position 31 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Jalili syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
22
DANN
Benign
0.87
DEOGEN2
Benign
0.077
T
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.23
T
M_CAP
Benign
0.046
D
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.24
Sift
Benign
0.070
T
Sift4G
Benign
0.16
T
Polyphen
0.0
B
Vest4
0.51
MutPred
0.62
Gain of disorder (P = 0.0014);
MVP
0.74
MPC
1.7
ClinPred
0.10
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.29
gMVP
0.71

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: rs760633483; hg19: chr2-97426827; API