8-64581023-C-G

Variant names:

• chr8-64581023-C-G
• NM_152414.5:c.233C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152414.5(BHLHE22):​c.233C>G​(p.Pro78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BHLHE22 NM_152414.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37494427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE22	NM_152414.5	c.233C>G	p.Pro78Arg	missense_variant	Exon 1 of 1	ENST00000321870.3	NP_689627.1
BHLHE22-AS1	NR_152770.1	n.175+695G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHLHE22	ENST00000321870.3	c.233C>G	p.Pro78Arg	missense_variant	Exon 1 of 1	6	NM_152414.5	ENSP00000318799.1
BHLHE22-AS1	ENST00000517909.1	n.171+695G>C		intron_variant	Intron 1 of 1	2
BHLHE22-AS1	ENST00000665275.1	n.94+695G>C		intron_variant	Intron 1 of 1
BHLHE22-AS1	ENST00000670034.1	n.204+695G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233C>G (p.P78R) alteration is located in exon 1 (coding exon 1) of the BHLHE22 gene. This alteration results from a C to G substitution at nucleotide position 233, causing the proline (P) at amino acid position 78 to be replaced by an arginine (R). 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	Benign	0.33
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.32
Sift	Benign	0.32	T
Sift4G	Benign	0.87	T
Polyphen		0.99	D
Vest4		0.32
MutPred		0.28		Gain of methylation at P78 (P = 0.0155);
MVP		0.50
MPC		1.1
ClinPred		0.46	T
GERP RS		2.2
Varity_R		0.14
gMVP		0.14

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-65493580;