8-60742620-G-T

Variant names:

• chr8-60742620-G-T
• rs201653177
• NM_017780.4:c.1188G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_017780.4(CHD7):​c.1188G>T​(p.Met396Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,612,636 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M396V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.37
• Publications: 8 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: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Orphanet
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013893217).
• BP6: Variant 8-60742620-G-T is Benign according to our data. Variant chr8-60742620-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 290788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000224 (327/1460526) while in subpopulation MID AF = 0.00399 (23/5766). AF 95% confidence interval is 0.00273. There are 1 homozygotes in GnomAdExome4. There are 165 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1188G>T	p.Met396Ile	missense	Exon 2 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1188G>T	p.Met396Ile	missense	Exon 1 of 5	NP_001303619.1	Q9P2D1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.1188G>T	p.Met396Ile	missense	Exon 2 of 38	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1188G>T	p.Met396Ile	missense	Exon 1 of 5	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.1188G>T	p.Met396Ile	missense	Exon 2 of 38	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152110 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000443 AC: 110 AN: 248486 AF XY: 0.000393

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1460526 Hom.: 1 Cov.: 32 AF XY: 0.000227 AC XY: 165 AN XY: 726364

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.0000448 AC: 2 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00860 AC: 224 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111030

Other (OTH) AF: 0.000663 AC: 40 AN: 60330

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152110 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000295

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000948 AC: 8

ExAC AF: 0.000322 AC: 39

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.69	N
PhyloP100		8.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D
Sift4G	Benign	0.18	T
Polyphen		0.85	P
Vest4		0.70
MutPred		0.25		Gain of catalytic residue at P398 (P = 0.0405)
MVP		0.85
MPC		0.12
ClinPred		0.12	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.30
Mutation Taster		=47/53	disease causing

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: rs201653177; hg19: chr8-61655179;