Genetic Variant KRT33B:p.Arg393Ser (chr17-41363874-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002279.5(KRT33B):c.1177C>A(p.Arg393Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,611,568 control chromosomes in the GnomAD database, including 2 homozygotes. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R393C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

KRT33B
NM_002279.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

3 publications found

Variant links:

Genes affected

KRT33B (HGNC:6451): (keratin 33B) This gene encodes a member of the keratin gene family. This gene is one of multiple type I hair keratin genes that are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. As a type I hair keratin, the encoded protein is an acidic protein which heterodimerizes with type II keratins to form hair and nails. There are two isoforms of this protein, encoded by two separate genes, keratin 33A and keratin 33B. [provided by RefSeq, May 2012]

KRT33B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072490275).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002279.5. 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
	KRT33B	NM_002279.5	MANE Select	c.1177C>A	p.Arg393Ser	missense	Exon 7 of 7	NP_002270.1	Q14525

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT33B	ENST00000251646.8	TSL:1 MANE Select	c.1177C>A	p.Arg393Ser	missense	Exon 7 of 7	ENSP00000251646.3	Q14525

Frequencies

GnomAD3 genomes

AF:

0.000371

AC:

AN:

151130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00490

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000519

AC:

130

AN:

250432

AF XY:

0.000598

show subpopulations

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:

0.00504

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000221

AC:

323

AN:

1460322

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

153

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33154

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

85880

European-Finnish (FIN)

AF:

0.00509

AC:

272

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111402

Other (OTH)

AF:

0.000232

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000370

AC:

AN:

151246

Hom.:

Cov.:

AF XY:

0.000514

AC XY:

AN XY:

73934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40578

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00490

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000954

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000420

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0052

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.13

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0072

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.6

PhyloP100

1.9

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.31

Sift

Benign

0.27

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.47

MVP

0.36

MPC

0.38

ClinPred

0.050

GERP RS

3.9

Varity_R

0.12

gMVP

0.44

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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