dbSNP rs369607220: KRT84:p.Arg588Leu (chr12-52378074-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_033045.4(KRT84):c.1763G>T(p.Arg588Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,343,328 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R588H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

KRT84
NM_033045.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.545

Publications

0 publications found

Variant links:

Genes affected

KRT84 (HGNC:6461): (keratin 84) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin is contained primarily in the filiform tongue papilla, among other hair keratins. [provided by RefSeq, Jul 2008]

KRT84 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033045.4. 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
	KRT84	NM_033045.4	MANE Select	c.1763G>T	p.Arg588Leu	missense	Exon 9 of 9	NP_149034.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT84	ENST00000257951.3	TSL:1 MANE Select	c.1763G>T	p.Arg588Leu	missense	Exon 9 of 9	ENSP00000257951.3	Q9NSB2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000143

AC:

AN:

139378

AF XY:

0.0000270

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:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000208

AC:

AN:

1343328

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

658196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28510

American (AMR)

AF:

0.00

AC:

AN:

26800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19484

East Asian (EAS)

AF:

0.00

AC:

AN:

34898

South Asian (SAS)

AF:

0.00

AC:

AN:

66426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4724

European-Non Finnish (NFE)

AF:

0.0000265

AC:

AN:

1058478

Other (OTH)

AF:

0.00

AC:

AN:

55182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.088

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.60

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.3

PhyloP100

0.55

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.014

Polyphen

0.89

Vest4

0.47

MutPred

0.56

Gain of catalytic residue at F589 (P = 5e-04)

MVP

0.67

MPC

0.030

ClinPred

0.71

GERP RS

1.9

Varity_R

0.13

gMVP

0.29

Mutation Taster

=77/23

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over