rs530700201

Variant names:

• chr14-21431306-G-A
• rs530700201
• NM_001170629.2:c.338C>T
• CHD8 p.Ser113Leu

Your query was ambiguous. Multiple possible variants found:

• chr14-21431306-G-A
• chr14-21431306-G-C
• chr14-21431306-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001170629.2(CHD8):​c.338C>T​(p.Ser113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 1,555,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S113W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: CHD8 NM_001170629.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.36
• Publications: 1 publications found

Genes affected

CHD8 (HGNC:20153): (chromodomain helicase DNA binding protein 8) This gene encodes a member of the chromodomain-helicase-DNA binding protein family, which is characterized by a SNF2-like domain and two chromatin organization modifier domains. The encoded protein also contains brahma and kismet domains, which are common to the subfamily of chromodomain-helicase-DNA binding proteins to which this protein belongs. This gene has been shown to function in several processes that include transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. Allelic variants of this gene are associated with autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

CHD8 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autism

  Inheritance: AD Classification: STRONG Submitted by: G2P
• intellectual developmental disorder with autism and macrocephaly

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• congenital myasthenic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06866288).
• BP6: Variant 14-21431306-G-A is Benign according to our data. Variant chr14-21431306-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521546.
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170629.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	NM_001170629.2	MANE Select	c.338C>T	p.Ser113Leu	missense	Exon 2 of 38	NP_001164100.1	Q9HCK8-1
	CHD8	NM_020920.4		c.6+505C>T		intron	N/A	NP_065971.2	Q9HCK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	ENST00000646647.2	MANE Select	c.338C>T	p.Ser113Leu	missense	Exon 2 of 38	ENSP00000495240.1	Q9HCK8-1
	CHD8	ENST00000430710.8	TSL:1	c.6+505C>T		intron	N/A	ENSP00000406288.3	Q9HCK8-2
	CHD8	ENST00000557364.6	TSL:5	c.338C>T	p.Ser113Leu	missense	Exon 2 of 38	ENSP00000451601.1	Q9HCK8-1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000377 AC: 6 AN: 159234 AF XY: 0.0000349

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000774

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.0000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000385 AC: 54 AN: 1403054 Hom.: 0 Cov.: 32 AF XY: 0.0000375 AC XY: 26 AN XY: 694224

African (AFR) AF: 0.000185 AC: 6 AN: 32380

American (AMR) AF: 0.000267 AC: 10 AN: 37410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25310

East Asian (EAS) AF: 0.00 AC: 0 AN: 37036

South Asian (SAS) AF: 0.0000495 AC: 4 AN: 80856

European-Finnish (FIN) AF: 0.0000550 AC: 2 AN: 36340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000275 AC: 30 AN: 1089312

Other (OTH) AF: 0.0000341 AC: 2 AN: 58688

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74482

African (AFR) AF: 0.000144 AC: 6 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Complex neurodevelopmental disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Uncertain	0.029	D
Sift4G	Benign	0.20	T
PromoterAI		-0.011	Neutral
Varity_R		0.082
gMVP		0.13
Mutation Taster		=82/18	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs530700201;

hg19: chr14-21899465;