rs34527521

Variant names:

• chr8-60853385-T-G
• rs34527521
• NM_017780.4:c.6660T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017780.4(CHD7):​c.6660T>G​(p.Gly2220Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,544,560 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.79
• Publications: 4 publications found

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]

CHD7 Gene-Disease associations (from GenCC):

• CHARGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• hypogonadotropic hypogonadism 5 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-60853385-T-G is Benign according to our data. Variant chr8-60853385-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00096 (146/152110) while in subpopulation NFE AF = 0.00196 (133/67982). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017780.4. 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
	CHD7	NM_017780.4	MANE Select	c.6660T>G	p.Gly2220Gly	synonymous	Exon 31 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1717-8844T>G		intron	N/A	NP_001303619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.6660T>G	p.Gly2220Gly	synonymous	Exon 31 of 38	ENSP00000392028.1
	CHD7	ENST00000524602.5	TSL:1	c.1717-8844T>G		intron	N/A	ENSP00000437061.1
	CHD7	ENST00000933299.1		c.6696T>G	p.Gly2232Gly	synonymous	Exon 31 of 38	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 146 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

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: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 205 AN: 191666 AF XY: 0.00103

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0000836

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000392

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.00114 AC: 1584 AN: 1392450 Hom.: 3 Cov.: 32 AF XY: 0.00106 AC XY: 725 AN XY: 686002

African (AFR) AF: 0.000292 AC: 9 AN: 30814

American (AMR) AF: 0.0000908 AC: 3 AN: 33030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21322

East Asian (EAS) AF: 0.00 AC: 0 AN: 39162

South Asian (SAS) AF: 0.00 AC: 0 AN: 73290

European-Finnish (FIN) AF: 0.000612 AC: 31 AN: 50620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 0.00139 AC: 1506 AN: 1081590

Other (OTH) AF: 0.000612 AC: 35 AN: 57220

GnomAD4 genome AF: 0.000960 AC: 146 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000713 AC XY: 53 AN XY: 74362

African (AFR) AF: 0.000193 AC: 8 AN: 41494

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.000827

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	CHARGE syndrome (1)
-	-	1	CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia (1)
-	-	1	Hypogonadotropic hypogonadism 5 with or without anosmia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.26
DANN	Benign	0.42
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs34527521; hg19: chr8-61765944;