rs34315566

Variant names:

• chr15-93009258-C-T
• rs34315566
• NM_001271.4:c.4527C>T
• CHD2 p.Ile1509Ile

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001271.4(CHD2):​c.4527C>T​(p.Ile1509Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.05 in 1,614,118 control chromosomes in the GnomAD database, including 2,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (239 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2473 hom.)
• Consequence: CHD2 NM_001271.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.60
• Publications: 5 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 15-93009258-C-T is Benign according to our data. Variant chr15-93009258-C-T is described in ClinVar as Benign. ClinVar VariationId is 257711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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.4527C>T	p.Ile1509Ile	synonymous	Exon 35 of 39	NP_001262.3	O14647-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	ENST00000394196.9	TSL:5 MANE Select	c.4527C>T	p.Ile1509Ile	synonymous	Exon 35 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.4527C>T	p.Ile1509Ile	synonymous	Exon 35 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000625662.3	TSL:5	n.*698C>T		non_coding_transcript_exon	Exon 31 of 35	ENSP00000486007.2	A0A0D9SEU0

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6311 AN: 152156 Hom.: 239 Cov.: 33

Gnomad AFR AF: 0.00902

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0588

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0441 AC: 11083 AN: 251356 AF XY: 0.0437

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.00724

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.0608

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0509 AC: 74370 AN: 1461844 Hom.: 2473 Cov.: 33 AF XY: 0.0499 AC XY: 36282 AN XY: 727226

African (AFR) AF: 0.00723 AC: 242 AN: 33478

American (AMR) AF: 0.00991 AC: 443 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00974 AC: 840 AN: 86250

European-Finnish (FIN) AF: 0.148 AC: 7912 AN: 53420

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.0559 AC: 62160 AN: 1111982

Other (OTH) AF: 0.0418 AC: 2524 AN: 60396

GnomAD4 genome AF: 0.0414 AC: 6309 AN: 152274 Hom.: 239 Cov.: 33 AF XY: 0.0435 AC XY: 3237 AN XY: 74446

African (AFR) AF: 0.00900 AC: 374 AN: 41566

American (AMR) AF: 0.0115 AC: 176 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4828

European-Finnish (FIN) AF: 0.153 AC: 1627 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0588 AC: 3998 AN: 68008

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0473 Hom.: 138

Bravo AF: 0.0291

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy 94 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.1
DANN	Benign	0.89
PhyloP100		-1.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=93/7	polymorphism (auto)

Splicing

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: rs34315566;

hg19: chr15-93552488;

COSMIC: COSV104431434;