Genetic Variant KLC3:p.Gly242Ser (chr19-45348105-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_177417.3(KLC3):c.724G>A(p.Gly242Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,170 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: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KLC3
NM_177417.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89

Publications

0 publications found

Variant links:

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]

KLC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLC3	NM_177417.3 link	c.724G>A	p.Gly242Ser	missense_variant	Exon 5 of 13	ENST00000391946.7	NP_803136.2	Q6P597-1A0A024R0V3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLC3	ENST00000391946.7 link	c.724G>A	p.Gly242Ser	missense_variant	Exon 5 of 13	1	NM_177417.3	ENSP00000375810.2		Q6P597-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

228480

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450170

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720470

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33242

American (AMR)

AF:

0.00

AC:

AN:

43204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25896

East Asian (EAS)

AF:

0.00

AC:

AN:

39230

South Asian (SAS)

AF:

0.00

AC:

AN:

84492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106916

Other (OTH)

AF:

0.0000167

AC:

AN:

59900

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.724G>A (p.G242S) alteration is located in exon 5 (coding exon 4) of the KLC3 gene. This alteration results from a G to A substitution at nucleotide position 724, causing the glycine (G) at amino acid position 242 to be replaced by a serine (S). 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

0.68

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.3

.;M;.;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.6

.;D;.;.;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.017

.;D;.;.;D

Sift4G

Uncertain

0.036

D;D;D;D;D

Polyphen

0.86, 0.84

.;P;P;.;P

Vest4

0.85, 0.85, 0.82

MutPred

0.74

Loss of catalytic residue at G242 (P = 0.0025);Loss of catalytic residue at G242 (P = 0.0025);.;.;.;

MVP

0.43

MPC

0.091

ClinPred

0.99

GERP RS

3.2

Varity_R

0.53

gMVP

0.62

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over