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GeneBe

19-18668584-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018316.3(KLHL26):c.1187T>C(p.Leu396Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

KLHL26
NM_018316.3 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70
Variant links:
Genes affected
KLHL26 (HGNC:25623): (kelch like family member 26)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KLHL26NM_018316.3 linkuse as main transcriptc.1187T>C p.Leu396Pro missense_variant 3/3 ENST00000300976.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KLHL26ENST00000300976.9 linkuse as main transcriptc.1187T>C p.Leu396Pro missense_variant 3/31 NM_018316.3 P1
KLHL26ENST00000599006.5 linkuse as main transcriptc.406-658T>C intron_variant 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.96e-7
AC:
1
AN:
1437226
Hom.:
0
Cov.:
33
AF XY:
0.00000140
AC XY:
1
AN XY:
714016
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.05e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 07, 2022The c.1187T>C (p.L396P) alteration is located in exon 3 (coding exon 3) of the KLHL26 gene. This alteration results from a T to C substitution at nucleotide position 1187, causing the leucine (L) at amino acid position 396 to be replaced by a proline (P). 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
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.95
P
Vest4
0.56
MutPred
0.82
Gain of catalytic residue at L396 (P = 0.0165);
MVP
0.97
MPC
1.9
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.91
gMVP
0.75

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: chr19-18779394; API