8-64580997-C-G

Variant names:

• chr8-64580997-C-G
• rs749889269
• NM_152414.5:c.207C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152414.5(BHLHE22):​c.207C>G​(p.Asp69Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,193,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: BHLHE22 NM_152414.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.720
• Publications: 0 publications found

Genes affected

BHLHE22 (HGNC:11963): (basic helix-loop-helix family member e22) This gene encodes a protein that belongs to the basic helix-loop-helix (bHLH) family of transcription factors that regulate cell fate determination, proliferation, and differentiation. A similar protein in mouse is required for the development of the dorsal cochlear nuclei, and is thought to play a role in in the differentiation of neurons involved in sensory input. The mouse protein also functions in retinogenesis. [provided by RefSeq, Oct 2016]

BHLHE22-AS1 (HGNC:56147): (BHLHE22 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1696485).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152414.5. 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
	BHLHE22	NM_152414.5	MANE Select	c.207C>G	p.Asp69Glu	missense	Exon 1 of 1	NP_689627.1	Q8NFJ8
	BHLHE22-AS1	NR_152770.1		n.175+721G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHE22	ENST00000321870.3	TSL:6 MANE Select	c.207C>G	p.Asp69Glu	missense	Exon 1 of 1	ENSP00000318799.1	Q8NFJ8
	BHLHE22-AS1	ENST00000517909.1	TSL:2	n.171+721G>C		intron	N/A
	BHLHE22-AS1	ENST00000665275.1		n.94+721G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1193780 Hom.: 0 Cov.: 34 AF XY: 0.00000346 AC XY: 2 AN XY: 577236

African (AFR) AF: 0.00 AC: 0 AN: 24370

American (AMR) AF: 0.00 AC: 0 AN: 11442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16484

East Asian (EAS) AF: 0.00 AC: 0 AN: 28388

South Asian (SAS) AF: 0.0000225 AC: 1 AN: 44404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3642

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 987416

Other (OTH) AF: 0.00 AC: 0 AN: 48704

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.72
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.28
Sift	Benign	0.16	T
Sift4G	Benign	0.40	T
Polyphen		0.056	B
Vest4		0.093
MutPred		0.17		Gain of glycosylation at P70 (P = 0.1051)
MVP		0.17
MPC		0.90
ClinPred		0.15	T
GERP RS		1.3
Varity_R		0.086
gMVP		0.10
Mutation Taster		=79/21	polymorphism

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: rs749889269; hg19: chr8-65493554;