rs773621487

Variant names:

• chr15-92941887-T-C
• rs773621487
• NM_001271.4:c.758T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001271.4(CHD2):​c.758T>C​(p.Val253Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V253I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.603
• Publications: 0 publications found

Genes affected

CHD2 (HGNC:1917): (chromodomain helicase DNA binding protein 2) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CHD2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 94

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03699693).
• BS2: High AC in GnomAdExome4 at 10 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271.4. 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
	CHD2	NM_001271.4	MANE Select	c.758T>C	p.Val253Ala	missense	Exon 8 of 39	NP_001262.3	O14647-1
	CHD2	NM_001042572.3		c.758T>C	p.Val253Ala	missense	Exon 8 of 13	NP_001036037.1	O14647-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	ENST00000394196.9	TSL:5 MANE Select	c.758T>C	p.Val253Ala	missense	Exon 8 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.758T>C	p.Val253Ala	missense	Exon 8 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000420239.7	TSL:1	c.758T>C	p.Val253Ala	missense	Exon 8 of 13	ENSP00000406581.2	O14647-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251056 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461006 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726864

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111476

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy 94 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.1
DANN	Benign	0.92
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.60
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.11
Sift	Benign	0.60	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.029
MVP		0.25
MPC		0.58
ClinPred		0.013	T
GERP RS		-1.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.028
gMVP		0.069
Mutation Taster		=96/4	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773621487; hg19: chr15-93485117;