14-23522236-C-G

Variant summary

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

The NM_033400.3(ZFHX2):​c.7445G>C​(p.Gly2482Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,322,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2482D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000015 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.634
Variant links:
Genes affected
ZFHX2 (HGNC:20152): (zinc finger homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in regulation of sensory perception of pain. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
ZFHX2-AS1 (HGNC:52658): (ZFHX2 antisense RNA 1)
THTPA (HGNC:18987): (thiamine triphosphatase) This gene encodes an enzyme which catalyzes the biosynthesis of thiamine disphophate (vitamin B1) by hydrolysis of thiamine triphosphate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

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=0.04553777).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZFHX2NM_033400.3 linkc.7445G>C p.Gly2482Ala missense_variant Exon 10 of 10 ENST00000419474.5 NP_207646.2 Q9C0A1-1B7ZM83A0A2P1H683B9EK48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZFHX2ENST00000419474.5 linkc.7445G>C p.Gly2482Ala missense_variant Exon 10 of 10 5 NM_033400.3 ENSP00000413418.2 Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkn.238+7820C>G intron_variant Intron 2 of 2 2
ZFHX2-AS1ENST00000554403.1 linkn.1068+7820C>G intron_variant Intron 1 of 2 2
ZFHX2-AS1ENST00000556354.5 linkn.465+7820C>G intron_variant Intron 4 of 4 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000151
AC:
2
AN:
1322482
Hom.:
0
Cov.:
36
AF XY:
0.00000155
AC XY:
1
AN XY:
645024
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000568
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.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
11
DANN
Benign
0.95
DEOGEN2
Benign
0.0069
T
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.65
T
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.046
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.69
N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.042
Sift
Benign
0.43
T
Sift4G
Benign
0.30
T
Polyphen
0.0010
B
Vest4
0.089
MutPred
0.32
Gain of catalytic residue at S2480 (P = 0);
MVP
0.048
ClinPred
0.15
T
GERP RS
1.6
Varity_R
0.052
gMVP
0.12

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: rs766572697; hg19: chr14-23991445; API