12-57525632-C-T

Variant summary

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

The NM_052897.4(MBD6):​c.664C>T​(p.Leu222Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000075 ( 0 hom. )

Consequence

MBD6
NM_052897.4 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.31
Variant links:
Genes affected
MBD6 (HGNC:20445): (methyl-CpG binding domain protein 6) Enables chromatin binding activity. Located in chromocenter; fibrillar center; and nucleoplasm. Implicated in autism spectrum disorder. [provided by Alliance of Genome Resources, Apr 2022]

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=0.22230557).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MBD6NM_052897.4 linkc.664C>T p.Leu222Phe missense_variant Exon 6 of 13 ENST00000355673.8 NP_443129.3 Q96DN6A0A024RBA3Q6P0P0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MBD6ENST00000355673.8 linkc.664C>T p.Leu222Phe missense_variant Exon 6 of 13 1 NM_052897.4 ENSP00000347896.3 Q96DN6
MBD6ENST00000552659.1 linkc.364+517C>T intron_variant Intron 3 of 4 3 ENSP00000446834.1 H0YHD1
MBD6ENST00000548887.5 linkc.*218C>T downstream_gene_variant 4 ENSP00000448070.1 F8VU14
MBD6ENST00000549623.1 linkc.*177C>T downstream_gene_variant 4 ENSP00000446481.1 F8VPC4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250912
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135652
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:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461686
Hom.:
0
Cov.:
35
AF XY:
0.00000688
AC XY:
5
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.664C>T (p.L222F) alteration is located in exon 6 (coding exon 4) of the MBD6 gene. This alteration results from a C to T substitution at nucleotide position 664, causing the leucine (L) at amino acid position 222 to be replaced by a phenylalanine (F). 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
0.15
BayesDel_addAF
Benign
-0.050
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.032
T
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.0034
T
MetaRNN
Benign
0.22
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.090
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.73
T
Polyphen
0.99
D
Vest4
0.40
MutPred
0.24
Gain of catalytic residue at N223 (P = 0);
MVP
0.043
MPC
0.049
ClinPred
0.42
T
GERP RS
3.4
Varity_R
0.20
gMVP
0.17

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: rs982498860; hg19: chr12-57919415; API