19-45351317-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_177417.3(KLC3):c.1475G>A(p.Arg492Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,612,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
KLC3
NM_177417.3 missense
NM_177417.3 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 3.09
Genes affected
KLC3 (HGNC:20717): (kinesin light chain 3) This gene encodes a member of the kinesin light chain gene family. Kinesins are molecular motors involved in the transport of cargo along microtubules, and are composed of two kinesin heavy chain (KHC) and two kinesin light chain (KLC) molecules. KLCs are thought to typically be involved in binding cargo and regulating kinesin activity. In the rat, a protein similar to this gene product is expressed in post-meiotic spermatids, where it associates with structural components of sperm tails and mitochondria. [provided by RefSeq, Jul 2008]
ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLC3 | NM_177417.3 | c.1475G>A | p.Arg492Gln | missense_variant | 13/13 | ENST00000391946.7 | |
ERCC2 | NM_000400.4 | c.*312C>T | 3_prime_UTR_variant | 23/23 | ENST00000391945.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLC3 | ENST00000391946.7 | c.1475G>A | p.Arg492Gln | missense_variant | 13/13 | 1 | NM_177417.3 | P4 | |
ERCC2 | ENST00000391945.10 | c.*312C>T | 3_prime_UTR_variant | 23/23 | 1 | NM_000400.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000132 AC: 20AN: 152078Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000141 AC: 35AN: 248046Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 134780
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GnomAD4 exome AF: 0.000100 AC: 146AN: 1460210Hom.: 0 Cov.: 37 AF XY: 0.000102 AC XY: 74AN XY: 726530
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GnomAD4 genome AF: 0.000132 AC: 20AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74294
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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 submitter | clinical testing | Ambry Genetics | Oct 03, 2022 | The c.1475G>A (p.R492Q) alteration is located in exon 13 (coding exon 12) of the KLC3 gene. This alteration results from a G to A substitution at nucleotide position 1475, causing the arginine (R) at amino acid position 492 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at