dbSNP rs797045462: CHD7:p.Ala685_Lys686dup (chr8-60781383-G-GAAAGCA) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM4PP3BP6_Very_StrongBS1BS2

The NM_017780.4(CHD7):c.2053_2058dupGCAAAA(p.Ala685_Lys686dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,539,622 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 6 hom., cov: 32)

Exomes 𝑓: 0.010 ( 69 hom. )

Consequence

CHD7
NM_017780.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 8.03

Publications

11 publications found

Variant links:

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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics, ClinGen
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

CHD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_017780.4.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 8-60781383-G-GAAAGCA is Benign according to our data. Variant chr8-60781383-G-GAAAGCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00772 (1175/152290) while in subpopulation NFE AF = 0.0119 (811/68030). AF 95% confidence interval is 0.0112. There are 6 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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.2053_2058dupGCAAAA	p.Ala685_Lys686dup	conservative_inframe_insertion	Exon 3 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1716+337_1716+342dupGCAAAA		intron	N/A	NP_001303619.1	Q9P2D1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD7	ENST00000423902.7	TSL:5 MANE Select	c.2053_2058dupGCAAAA	p.Ala685_Lys686dup	conservative_inframe_insertion	Exon 3 of 38	ENSP00000392028.1	Q9P2D1-1
CHD7	ENST00000524602.5	TSL:1	c.1716+337_1716+342dupGCAAAA		intron	N/A	ENSP00000437061.1	Q9P2D1-4
CHD7	ENST00000933299.1		c.2053_2058dupGCAAAA	p.Ala685_Lys686dup	conservative_inframe_insertion	Exon 3 of 38	ENSP00000603358.1

Frequencies

GnomAD3 genomes

AF:

0.00772

AC:

1175

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00623

AC:

960

AN:

154032

AF XY:

0.00569

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00752

Gnomad ASJ exome

AF:

0.00432

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00299

Gnomad NFE exome

AF:

0.00979

Gnomad OTH exome

AF:

0.00659

GnomAD4 exome

AF:

0.0101

AC:

14049

AN:

1387332

Hom.:

Cov.:

AF XY:

0.00985

AC XY:

6752

AN XY:

685424

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

29624

American (AMR)

AF:

0.00713

AC:

195

AN:

27342

Ashkenazi Jewish (ASJ)

AF:

0.00531

AC:

124

AN:

23364

East Asian (EAS)

AF:

0.00

AC:

AN:

37038

South Asian (SAS)

AF:

0.00117

AC:

AN:

72936

European-Finnish (FIN)

AF:

0.00351

AC:

175

AN:

49908

Middle Eastern (MID)

AF:

0.00852

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.0119

AC:

12856

AN:

1084166

Other (OTH)

AF:

0.00911

AC:

523

AN:

57436

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

775

1549

2324

3098

3873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00772

AC:

1175

AN:

152290

Hom.:

Cov.:

AF XY:

0.00770

AC XY:

573

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41560

American (AMR)

AF:

0.0100

AC:

153

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00104

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

811

AN:

68030

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00979

Hom.:

Bravo

AF:

0.00841

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (6)

CHARGE syndrome (3)

Hypogonadism with anosmia (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=26/74

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over