2-96761070-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020184.4(CNNM4):​c.71C>T​(p.Pro24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CNNM4
NM_020184.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.579
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.054251254).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNNM4NM_020184.4 linkuse as main transcriptc.71C>T p.Pro24Leu missense_variant 1/7 ENST00000377075.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM4ENST00000377075.3 linkuse as main transcriptc.71C>T p.Pro24Leu missense_variant 1/71 NM_020184.4 P1Q6P4Q7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1131470
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
539420
Gnomad4 AFR exome
AF:
0.00
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
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 19, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1445304). This variant has not been reported in the literature in individuals affected with CNNM4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 24 of the CNNM4 protein (p.Pro24Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
15
DANN
Benign
0.87
DEOGEN2
Benign
0.031
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.39
T
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.054
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-1.2
N
MutationTaster
Benign
0.92
N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
1.1
N
REVEL
Benign
0.094
Sift
Benign
0.18
T
Sift4G
Benign
0.88
T
Polyphen
0.0
B
Vest4
0.052
MutPred
0.38
Gain of MoRF binding (P = 0.0572);
MVP
0.24
MPC
1.1
ClinPred
0.090
T
GERP RS
0.63
Varity_R
0.032
gMVP
0.24

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: rs771910068; hg19: chr2-97426807; API