rs3212102

Positions:

• chr14-103700657-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_001394837.1(KLC1):​c.1851C>T​(p.Gly617=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,606,024 control chromosomes in the GnomAD database, including 502 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 34)
  • Exomes 𝑓: 0.024 (470 hom.)
• Consequence: KLC1 NM_001394837.1 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.658

Genes affected

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

XRCC3 (HGNC:12830): (X-ray repair cross complementing 3) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002668649).
• BP7: Synonymous conserved (PhyloP=-0.658 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2634/152376) while in subpopulation NFE AF= 0.0266 (1806/68022). AF 95% confidence interval is 0.0255. There are 32 homozygotes in gnomad4. There are 1252 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2634 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLC1	NM_001394837.1	c.1851C>T	p.Gly617=	splice_region_variant, synonymous_variant	16/17	ENST00000334553.11
XRCC3	NM_005432.4	c.562-1081G>A		intron_variant		ENST00000555055.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLC1	ENST00000334553.11	c.1851C>T	p.Gly617=	splice_region_variant, synonymous_variant	16/17	5	NM_001394837.1
XRCC3	ENST00000555055.6	c.562-1081G>A		intron_variant		1	NM_005432.4	P1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2634 AN: 152258 Hom.: 32 Cov.: 34

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0177 AC: 4296 AN: 242474 Hom.: 48 AF XY: 0.0177 AC XY: 2336 AN XY: 132244

Gnomad AFR exome AF: 0.00533

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.000292

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0240 AC: 34830 AN: 1453648 Hom.: 470 Cov.: 30 AF XY: 0.0236 AC XY: 17102 AN XY: 723196

Gnomad4 AFR exome AF: 0.00364

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0226

Gnomad4 NFE exome AF: 0.0270

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0173 AC: 2634 AN: 152376 Hom.: 32 Cov.: 34 AF XY: 0.0168 AC XY: 1252 AN XY: 74514

Gnomad4 AFR AF: 0.00502

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0266

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0232 Hom.: 93

Bravo AF: 0.0161

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.00527 AC: 21

ESP6500EA AF: 0.0235 AC: 195

ExAC AF: 0.0177 AC: 2137

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.8
DANN	Benign	0.97
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.46	N;N
REVEL	Benign	0.10
Sift	Benign	0.052	T;D
Sift4G	Benign	0.15	T;T
Vest4		0.091
MPC		0.38
ClinPred		0.0032	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs3212102; hg19: chr14-104166994;