rs2272727

Variant names:

• chr8-60856636-A-G
• rs2272727
• NM_017780.4:c.7356A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017780.4(CHD7):​c.7356A>G​(p.Thr2452Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.0546 in 1,614,006 control chromosomes in the GnomAD database, including 2,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (156 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2498 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.53
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 8-60856636-A-G is Benign according to our data. Variant chr8-60856636-A-G is described in ClinVar as Benign. ClinVar VariationId is 95811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

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.7356A>G	p.Thr2452Thr	synonymous	Exon 34 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1717-5593A>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.7356A>G	p.Thr2452Thr	synonymous	Exon 34 of 38	ENSP00000392028.1
	CHD7	ENST00000524602.5	TSL:1	c.1717-5593A>G		intron	N/A	ENSP00000437061.1
	CHD7	ENST00000933299.1		c.7389A>G	p.Thr2463Thr	synonymous	Exon 34 of 38	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6282 AN: 152200 Hom.: 156 Cov.: 33

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0526

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0462 AC: 11522 AN: 249274 AF XY: 0.0475

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0516

Gnomad FIN exome AF: 0.0591

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0560 AC: 81855 AN: 1461688 Hom.: 2498 Cov.: 32 AF XY: 0.0556 AC XY: 40420 AN XY: 727128

African (AFR) AF: 0.0128 AC: 430 AN: 33480

American (AMR) AF: 0.0234 AC: 1046 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 705 AN: 26136

East Asian (EAS) AF: 0.0481 AC: 1909 AN: 39700

South Asian (SAS) AF: 0.0385 AC: 3320 AN: 86258

European-Finnish (FIN) AF: 0.0562 AC: 3001 AN: 53402

Middle Eastern (MID) AF: 0.0348 AC: 201 AN: 5768

European-Non Finnish (NFE) AF: 0.0613 AC: 68111 AN: 1111846

Other (OTH) AF: 0.0519 AC: 3132 AN: 60374

GnomAD4 genome AF: 0.0412 AC: 6281 AN: 152318 Hom.: 156 Cov.: 33 AF XY: 0.0409 AC XY: 3043 AN XY: 74474

African (AFR) AF: 0.0141 AC: 585 AN: 41588

American (AMR) AF: 0.0288 AC: 441 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.0527 AC: 273 AN: 5176

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4828

European-Finnish (FIN) AF: 0.0571 AC: 606 AN: 10604

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0574 AC: 3904 AN: 68024

Other (OTH) AF: 0.0492 AC: 104 AN: 2114

Alfa AF: 0.0507 Hom.: 434

Bravo AF: 0.0389

Asia WGS AF: 0.0620 AC: 215 AN: 3478

EpiCase AF: 0.0547

EpiControl AF: 0.0562

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	CHARGE syndrome (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	-0.49
CADD	Benign	8.4
DANN	Benign	0.73
PhyloP100		4.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2272727; hg19: chr8-61769195; COSMIC: COSV101418019; COSMIC: COSV101418019;