20-41405149-A-G

Position:

• chr20-41405149-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032221.5(CHD6):​c.7592T>C​(p.Met2531Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHD6 NM_032221.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.78

Genes affected

CHD6 (HGNC:19057): (chromodomain helicase DNA binding protein 6) This gene encodes a member of the SNF2/RAD54 helicase protein family. The encoded protein contains two chromodomains, a helicase domain, and an ATPase domain. Several multi-subunit protein complexes remodel chromatin to allow patterns of cell type-specific gene expression, and the encoded protein is thought to be a core member of one or more of these chromatin remodeling complexes. The encoded protein may function as a transcriptional repressor and is involved in the cellular repression of influenza virus replication. [provided by RefSeq, Jul 2013]

CHD6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD6	NM_032221.5	c.7592T>C	p.Met2531Thr	missense_variant	37/37	ENST00000373233.8	NP_115597.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD6	ENST00000373233.8	c.7592T>C	p.Met2531Thr	missense_variant	37/37	1	NM_032221.5	ENSP00000362330.3
CHD6	ENST00000480022.1	n.2203T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.7592T>C (p.M2531T) alteration is located in exon 37 (coding exon 36) of the CHD6 gene. This alteration results from a T to C substitution at nucleotide position 7592, causing the methionine (M) at amino acid position 2531 to be replaced by a threonine (T). 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	P
Vest4		0.66
MutPred		0.27		Gain of glycosylation at M2531 (P = 0.0418);
MVP		0.75
MPC		0.69
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-40033789;