19-45350548-A-C

Position:

• chr19-45350548-A-C

Variant summary

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

The NM_177417.3(KLC3):​c.1269A>C​(p.Glu423Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KLC3 NM_177417.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.48

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=0.071612686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLC3	NM_177417.3	c.1269A>C	p.Glu423Asp	missense_variant	10/13	ENST00000391946.7	NP_803136.2
ERCC2	NM_000400.4	c.*1081T>G		3_prime_UTR_variant	23/23	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLC3	ENST00000391946.7	c.1269A>C	p.Glu423Asp	missense_variant	10/13	1	NM_177417.3	ENSP00000375810	P4
ERCC2	ENST00000391945.10	c.*1081T>G		3_prime_UTR_variant	23/23	1	NM_000400.4	ENSP00000375809	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

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

Dec 15, 2022

The c.1269A>C (p.E423D) alteration is located in exon 10 (coding exon 9) of the KLC3 gene. This alteration results from a A to C substitution at nucleotide position 1269, causing the glutamic acid (E) at amino acid position 423 to be replaced by an aspartic acid (D). 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	0.084
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.79
DANN	Benign	0.76
DEOGEN2	Benign	0.060	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.27	T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	0.70	D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.97	N;.;N
REVEL	Benign	0.11
Sift	Benign	0.35	T;.;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.034	B;B;B
Vest4		0.13
MutPred		0.23		Loss of helix (P = 0.1299);.;.;
MVP		0.46
MPC		0.012
ClinPred		0.14	T
GERP RS		-6.0
Varity_R		0.050
gMVP		0.47

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: chr19-45853806;