2-96761033-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020184.4(CNNM4):​c.34G>T​(p.Gly12Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000247 in 1,215,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

CNNM4
NM_020184.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNNM4NM_020184.4 linkuse as main transcriptc.34G>T p.Gly12Cys missense_variant 1/7 ENST00000377075.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM4ENST00000377075.3 linkuse as main transcriptc.34G>T p.Gly12Cys missense_variant 1/71 NM_020184.4 P1Q6P4Q7-1

Frequencies

GnomAD3 genomes
AF:
0.00000668
AC:
1
AN:
149752
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000188
AC:
2
AN:
1066032
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
503418
show subpopulations
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:
0.00000220
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000668
AC:
1
AN:
149752
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
73014
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000149
Gnomad4 OTH
AF:
0.00

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 submitterclinical testingAmbry GeneticsAug 15, 2023The c.34G>T (p.G12C) alteration is located in exon 1 (coding exon 1) of the CNNM4 gene. This alteration results from a G to T substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a cysteine (C). 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
0.18
BayesDel_addAF
Uncertain
0.015
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
17
DANN
Benign
0.88
DEOGEN2
Benign
0.036
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.34
N
LIST_S2
Benign
0.35
T
M_CAP
Pathogenic
0.86
D
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.13
Sift
Benign
0.097
T
Sift4G
Uncertain
0.032
D
Polyphen
0.85
P
Vest4
0.37
MutPred
0.36
Loss of disorder (P = 0.0291);
MVP
0.71
MPC
1.1
ClinPred
0.34
T
GERP RS
1.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.0
Varity_R
0.23
gMVP
0.49

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: rs1171352404; hg19: chr2-97426770; API