19-45350647-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177417.3(KLC3):c.1279C>T(p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,613,644 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: KLC3 NM_177417.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15586409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLC3	NM_177417.3	c.1279C>T	p.Arg427Cys	missense_variant	11/13	ENST00000391946.7
ERCC2	NM_000400.4	c.*982G>A		3_prime_UTR_variant	23/23	ENST00000391945.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLC3	ENST00000391946.7	c.1279C>T	p.Arg427Cys	missense_variant	11/13	1	NM_177417.3	P4
ERCC2	ENST00000391945.10	c.*982G>A		3_prime_UTR_variant	23/23	1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152072 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000807 AC: 20 AN: 247904 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134718

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461454 Hom.: 0 Cov.: 34 AF XY: 0.0000564 AC XY: 41 AN XY: 727012

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152190 Hom.: 0 Cov.: 30 AF XY: 0.0000403 AC XY: 3 AN XY: 74394

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000910 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.1279C>T (p.R427C) alteration is located in exon 11 (coding exon 10) of the KLC3 gene. This alteration results from a C to T substitution at nucleotide position 1279, causing the arginine (R) at amino acid position 427 to be replaced by a cysteine (C). 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	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.53
MVP		0.85
MPC		0.018
ClinPred		0.17	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs201950695; hg19: chr19-45853905;