8-60848612-C-T

Position:

• chr8-60848612-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017780.4(CHD7):​c.5300+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,605,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: CHD7 NM_017780.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002491
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.519

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 8-60848612-C-T is Benign according to our data. Variant chr8-60848612-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 287628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.5300+8C>T		splice_region_variant, intron_variant		ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.5300+8C>T		splice_region_variant, intron_variant		5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-13617C>T		intron_variant		1		ENSP00000437061.1
CHD7	ENST00000695853.1	n.5300+8C>T		splice_region_variant, intron_variant				ENSP00000512218.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000864 AC: 212 AN: 245346 Hom.: 1 AF XY: 0.000834 AC XY: 111 AN XY: 133026

Gnomad AFR exome AF: 0.000400

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000341

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000529 AC: 768 AN: 1452876 Hom.: 3 Cov.: 28 AF XY: 0.000548 AC XY: 396 AN XY: 723074

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74456

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.000521

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 10, 2016

- -

CHARGE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

CHD7: BP4, BS1 -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.0
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs151322460; hg19: chr8-61761171;