Genetic Variant NM_152414.5:c.269G>T (chr8-64581059-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152414.5(BHLHE22):c.269G>T(p.Ser90Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,325,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

BHLHE22
NM_152414.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.994

Publications

0 publications found

Variant links:

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 links:

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

BHLHE22-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09016296).

BS2

High AC in GnomAd4 at 13 AD gene.

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.269G>T	p.Ser90Ile	missense	Exon 1 of 1	NP_689627.1	Q8NFJ8
	BHLHE22-AS1	NR_152770.1		n.175+659C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BHLHE22	ENST00000321870.3	TSL:6 MANE Select	c.269G>T	p.Ser90Ile	missense	Exon 1 of 1	ENSP00000318799.1	Q8NFJ8
BHLHE22-AS1	ENST00000517909.1	TSL:2	n.171+659C>A		intron	N/A
BHLHE22-AS1	ENST00000665275.1		n.94+659C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000872

AC:

AN:

149010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000276

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.000488

GnomAD4 exome

AF:

0.00000680

AC:

AN:

1176786

Hom.:

Cov.:

AF XY:

0.00000704

AC XY:

AN XY:

568332

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

23618

American (AMR)

AF:

0.000111

AC:

AN:

8978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15954

East Asian (EAS)

AF:

0.00

AC:

AN:

27406

South Asian (SAS)

AF:

0.00

AC:

AN:

40342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3404

European-Non Finnish (NFE)

AF:

0.00000204

AC:

AN:

981760

Other (OTH)

AF:

0.0000415

AC:

AN:

48238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000872

AC:

AN:

149102

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

72886

show subpopulations

African (AFR)

AF:

0.000275

AC:

AN:

39968

American (AMR)

AF:

0.00

AC:

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5090

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67154

Other (OTH)

AF:

0.000483

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000529

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.086

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.28

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.090

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

0.0

PhyloP100

0.99

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.37

REVEL

Benign

0.28

Sift

Uncertain

0.0080

Sift4G

Benign

0.068

Polyphen

0.085

Vest4

0.22

MutPred

0.17

Loss of glycosylation at S90 (P = 0.0022)

MVP

0.30

MPC

1.1

ClinPred

0.20

GERP RS

2.1

Varity_R

0.098

gMVP

0.30

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over