NM_017780.4:c.216T>C

Variant names:

• chr8-60741648-T-C
• rs16926453
• NM_017780.4:c.216T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):​c.216T>C​(p.Tyr72Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.00173 in 1,613,810 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.93
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-60741648-T-C is Benign according to our data. Variant chr8-60741648-T-C is described in ClinVar as Benign. ClinVar VariationId is 95778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00222 (338/152354) while in subpopulation AMR AF = 0.0156 (238/15304). AF 95% confidence interval is 0.0139. There are 1 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 51 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.216T>C	p.Tyr72Tyr	synonymous	Exon 2 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.216T>C	p.Tyr72Tyr	synonymous	Exon 1 of 5	NP_001303619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.216T>C	p.Tyr72Tyr	synonymous	Exon 2 of 38	ENSP00000392028.1
	CHD7	ENST00000524602.5	TSL:1	c.216T>C	p.Tyr72Tyr	synonymous	Exon 1 of 5	ENSP00000437061.1
	CHD7	ENST00000933299.1		c.216T>C	p.Tyr72Tyr	synonymous	Exon 2 of 38	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 331 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00723 AC: 1798 AN: 248656 AF XY: 0.00563

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0420

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0116

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.000754

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00168 AC: 2457 AN: 1461456 Hom.: 51 Cov.: 32 AF XY: 0.00147 AC XY: 1067 AN XY: 726974

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.0387 AC: 1727 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00743 AC: 295 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86200

European-Finnish (FIN) AF: 0.00262 AC: 140 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000165 AC: 183 AN: 1111760

Other (OTH) AF: 0.00156 AC: 94 AN: 60370

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152354 Hom.: 1 Cov.: 32 AF XY: 0.00256 AC XY: 191 AN XY: 74500

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.0156 AC: 238 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68038

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00223 Hom.: 5

Bravo AF: 0.00434

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	CHARGE syndrome (2)
-	-	2	not provided (2)
-	-	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	-0.54
CADD	Benign	7.7
DANN	Benign	0.55
PhyloP100		4.9
PromoterAI		0.023	Neutral
Mutation Taster		=95/5	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: rs16926453; hg19: chr8-61654207;