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GeneBe

17-41567477-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_000226.4(KRT9):c.1668C>A(p.Gly556=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,531,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 29)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

KRT9
NM_000226.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.615
Variant links:
Genes affected
KRT9 (HGNC:6447): (keratin 9) This gene encodes the type I keratin 9, an intermediate filament chain expressed only in the terminally differentiated epidermis of palms and soles. Mutations in this gene cause epidermolytic palmoplantar keratoderma. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-41567477-G-T is Benign according to our data. Variant chr17-41567477-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3034210.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.615 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000302 (40/132468) while in subpopulation NFE AF= 0.000504 (32/63548). AF 95% confidence interval is 0.000366. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRT9NM_000226.4 linkuse as main transcriptc.1668C>A p.Gly556= synonymous_variant 7/8 ENST00000246662.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRT9ENST00000246662.9 linkuse as main transcriptc.1668C>A p.Gly556= synonymous_variant 7/81 NM_000226.4 P1
KRT9ENST00000588431.1 linkuse as main transcriptc.969C>A p.Gly323= synonymous_variant 8/91

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000302
AC:
40
AN:
132468
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.000119
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000798
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000384
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000504
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000204
AC:
32
AN:
156660
Hom.:
0
AF XY:
0.000206
AC XY:
17
AN XY:
82466
show subpopulations
Gnomad AFR exome
AF:
0.000112
Gnomad AMR exome
AF:
0.0000402
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000645
Gnomad NFE exome
AF:
0.000469
Gnomad OTH exome
AF:
0.000222
GnomAD4 exome
AF:
0.000274
AC:
383
AN:
1399126
Hom.:
0
Cov.:
148
AF XY:
0.000256
AC XY:
177
AN XY:
690162
show subpopulations
Gnomad4 AFR exome
AF:
0.000128
Gnomad4 AMR exome
AF:
0.0000840
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000202
Gnomad4 NFE exome
AF:
0.000330
Gnomad4 OTH exome
AF:
0.000172
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000302
AC:
40
AN:
132468
Hom.:
0
Cov.:
29
AF XY:
0.000253
AC XY:
16
AN XY:
63362
show subpopulations
Gnomad4 AFR
AF:
0.000119
Gnomad4 AMR
AF:
0.0000798
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000384
Gnomad4 NFE
AF:
0.000504
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000249
Hom.:
0

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

KRT9-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 20, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
Cadd
Benign
0.99
Dann
Benign
0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369406178; hg19: chr17-39723729; API