8-64581079-G-C

Variant names:

• chr8-64581079-G-C
• rs1274515933
• NM_152414.5:c.289G>C

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.289G>C​(p.Gly97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000852 in 1,174,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 8.5e-7 (0 hom.)
• Consequence: BHLHE22 NM_152414.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.151
• 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=0.2233786).

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.289G>C	p.Gly97Arg	missense	Exon 1 of 1	NP_689627.1	Q8NFJ8
	BHLHE22-AS1	NR_152770.1		n.175+639C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHE22	ENST00000321870.3	TSL:6 MANE Select	c.289G>C	p.Gly97Arg	missense	Exon 1 of 1	ENSP00000318799.1	Q8NFJ8
	BHLHE22-AS1	ENST00000517909.1	TSL:2	n.171+639C>G		intron	N/A
	BHLHE22-AS1	ENST00000665275.1		n.94+639C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.52e-7 AC: 1 AN: 1174370 Hom.: 0 Cov.: 35 AF XY: 0.00000177 AC XY: 1 AN XY: 566530

African (AFR) AF: 0.00 AC: 0 AN: 23614

American (AMR) AF: 0.00 AC: 0 AN: 9182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15956

East Asian (EAS) AF: 0.00 AC: 0 AN: 27420

South Asian (SAS) AF: 0.00 AC: 0 AN: 40002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3470

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 979824

Other (OTH) AF: 0.00 AC: 0 AN: 48110

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.69	N
PhyloP100		0.15
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.37		Gain of methylation at G97 (P = 0.0043)
MVP		0.20
MPC		2.2
ClinPred		0.81	D
Varity_R		0.16
gMVP		0.27
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1274515933; hg19: chr8-65493636;