rs146944583

Variant names:

• chr15-92974957-T-C
• rs146944583
• NM_001271.4:c.2577+7T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-92974957-T-C
• chr15-92974957-T-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001271.4(CHD2):​c.2577+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,612,200 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: CHD2 NM_001271.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001672
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.62
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-92974957-T-C is Benign according to our data. Variant chr15-92974957-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 550 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.2577+7T>C		splice_region intron	N/A	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.2577+7T>C		splice_region intron	N/A	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.2577+7T>C		splice_region intron	N/A	ENSP00000486629.1	O14647-2
	CHD2	ENST00000625463.1	TSL:1	c.117+7T>C		splice_region intron	N/A	ENSP00000486391.1	A0A0D9SF92

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 550 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00354 AC: 883 AN: 249424 AF XY: 0.00372

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00511 AC: 7459 AN: 1459874 Hom.: 27 Cov.: 29 AF XY: 0.00508 AC XY: 3687 AN XY: 726322

African (AFR) AF: 0.000778 AC: 26 AN: 33408

American (AMR) AF: 0.00296 AC: 132 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86134

European-Finnish (FIN) AF: 0.00309 AC: 165 AN: 53384

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00608 AC: 6751 AN: 1110536

Other (OTH) AF: 0.00403 AC: 243 AN: 60318

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74500

African (AFR) AF: 0.00111 AC: 46 AN: 41570

American (AMR) AF: 0.00203 AC: 31 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00564 AC: 384 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00409 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Developmental and epileptic encephalopathy 94 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.5
DANN	Benign	0.82
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.014
Splicevardb		1.0

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

Other links and lift over

dbSNP: rs146944583; hg19: chr15-93518187; COSMIC: COSV104431366;