19-45350543-G-T

Variant names:

• chr19-45350543-G-T
• rs199738278
• NM_177417.3:c.1264G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_177417.3(KLC3):​c.1264G>T​(p.Ala422Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A422T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLC3 NM_177417.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.90
• Publications: 0 publications found

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]

ERCC2 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, ClinGen
• sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05453506).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177417.3. 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
	KLC3	NM_177417.3	MANE Select	c.1264G>T	p.Ala422Ser	missense	Exon 10 of 13	NP_803136.2	Q6P597-1
	ERCC2	NM_000400.4	MANE Select	c.*1086C>A		3_prime_UTR	Exon 23 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.*1086C>A		3_prime_UTR	Exon 23 of 23	NP_001427284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC3	ENST00000391946.7	TSL:1 MANE Select	c.1264G>T	p.Ala422Ser	missense	Exon 10 of 13	ENSP00000375810.2	Q6P597-1
	KLC3	ENST00000470402.1	TSL:1	c.1306G>T	p.Ala436Ser	missense	Exon 9 of 12	ENSP00000436019.1	Q6P597-3
	KLC3	ENST00000585434.5	TSL:1	c.1261G>T	p.Ala421Ser	missense	Exon 10 of 13	ENSP00000466067.1	Q6P597-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249524 AF XY: 0.00000739

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.013
DANN	Benign	0.59
DEOGEN2	Benign	0.044	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-3.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.18
Sift	Benign	0.56	T
Sift4G	Benign	0.75	T
Polyphen		0.020	B
Vest4		0.21
MutPred		0.40		Gain of phosphorylation at A422 (P = 0.0336)
MVP		0.39
MPC		0.012
ClinPred		0.044	T
GERP RS		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.029
gMVP		0.47
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs199738278; hg19: chr19-45853801;