12-57525632-C-T

Variant names:

• chr12-57525632-C-T
• rs982498860
• NM_052897.4:c.664C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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]

ACMG classification

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
MBD6	NM_052897.4	c.664C>T	p.Leu222Phe	missense_variant	Exon 6 of 13	ENST00000355673.8	NP_443129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD6	ENST00000355673.8	c.664C>T	p.Leu222Phe	missense_variant	Exon 6 of 13	1	NM_052897.4	ENSP00000347896.3
MBD6	ENST00000552659.1	c.364+517C>T		intron_variant	Intron 3 of 4	3		ENSP00000446834.1
MBD6	ENST00000548887.5	c.*218C>T		downstream_gene_variant		4		ENSP00000448070.1
MBD6	ENST00000549623.1	c.*177C>T		downstream_gene_variant		4		ENSP00000446481.1

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

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

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

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

Other links and lift over

dbSNP: rs982498860; hg19: chr12-57919415;