rs3212102

Variant names:

• chr14-103700657-C-T
• rs3212102
• NM_001394837.1:c.1851C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001394836.1(KLC1):​c.1859C>T​(p.Ala620Val) variant causes a missense, splice region 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. 15/19 in silico tools predict 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_001394836.1 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.658
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002668649).
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2634 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394836.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC1	NM_001394837.1	MANE Select	c.1851C>T	p.Gly617Gly	splice_region synonymous	Exon 16 of 17	NP_001381766.1	Q07866-9
	XRCC3	NM_005432.4	MANE Select	c.562-1081G>A		intron	N/A	NP_005423.1	O43542
	KLC1	NM_001394836.1		c.1859C>T	p.Ala620Val	missense splice_region	Exon 15 of 16	NP_001381765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC1	ENST00000334553.11	TSL:5 MANE Select	c.1851C>T	p.Gly617Gly	splice_region synonymous	Exon 16 of 17	ENSP00000334523.6	Q07866-9
	KLC1	ENST00000348520.10	TSL:1	c.1653C>T	p.Gly551Gly	splice_region synonymous	Exon 14 of 15	ENSP00000341154.6	Q07866-1
	XRCC3	ENST00000555055.6	TSL:1 MANE Select	c.562-1081G>A		intron	N/A	ENSP00000452598.1	O43542

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

GnomAD2 exomes AF: 0.0177 AC: 4296 AN: 242474 AF XY: 0.0177

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 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

African (AFR) AF: 0.00364 AC: 120 AN: 32928

American (AMR) AF: 0.0114 AC: 495 AN: 43474

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 656 AN: 25956

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39150

South Asian (SAS) AF: 0.0116 AC: 992 AN: 85526

European-Finnish (FIN) AF: 0.0226 AC: 1180 AN: 52246

Middle Eastern (MID) AF: 0.00576 AC: 32 AN: 5558

European-Non Finnish (NFE) AF: 0.0270 AC: 29969 AN: 1108782

Other (OTH) AF: 0.0230 AC: 1380 AN: 60028

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

African (AFR) AF: 0.00502 AC: 209 AN: 41596

American (AMR) AF: 0.0121 AC: 185 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4830

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0266 AC: 1806 AN: 68022

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0226 Hom.: 192

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.8
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.89	T
PhyloP100		-0.66
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.10
Sift	Benign	0.052	T
Sift4G	Benign	0.15	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
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs3212102; hg19: chr14-104166994;