8-60742620-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017780.4(CHD7):​c.1188G>A​(p.Met396Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.1188G>A	p.Met396Ile	missense_variant	Exon 2 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.1188G>A	p.Met396Ile	missense_variant	Exon 2 of 38	5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248486 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460526 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726364

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86174

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111030

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1188G>A (p.M396I) alteration is located in exon 2 (coding exon 1) of the CHD7 gene. This alteration results from a G to A substitution at nucleotide position 1188, causing the methionine (M) at amino acid position 396 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.12	D
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	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.69	N;N;N
PhyloP100		8.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.63	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.85	P;.;.
Vest4		0.70
MutPred		0.25		Gain of catalytic residue at P398 (P = 0.0405);Gain of catalytic residue at P398 (P = 0.0405);Gain of catalytic residue at P398 (P = 0.0405);
MVP		0.85
MPC		0.12
ClinPred		0.54	D
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; COSMIC: COSV105938475; COSMIC: COSV105938475;