NM_001244008.2:c.4612C>T

Variant names:

• chr2-240722509-G-A
• rs200184619
• NM_001244008.2:c.4612C>T
• KIF1A p.Arg1538Cys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). BP4_ModerateBP6

The NM_001244008.2(KIF1A):c.4612C>T (p.Arg1538Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000348 (AC=538) in the gnomAD database across 1,548,000 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00402. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1538H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1355067) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.67
• Publications: 1 publications found

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 30

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• spastic paraplegia 30A, autosomal dominant

  Inheritance: AD, AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KIF1A NM_001244008.2	MANE Select	c.4612C>T p.Arg1538Cys	missense	Exon 43 of 49	Prot: NP_001230937.1 UniProt:
	KIF1A NM_001379631.1		c.4687C>T p.Arg1563Cys	missense	Exon 43 of 49	Prot: NP_001366560.1
	KIF1A NM_001379642.1		c.4612C>T p.Arg1538Cys	missense	Exon 43 of 49	Prot: NP_001366571.1

KIF1A NM_001244008.2

MANE Select

HGVSc / HGVSpc.4612C>Tp.Arg1538Cys

Exon rankExon 43 of 49

missense

Prot: NP_001230937.1UniProt: Q12756-3

KIF1A NM_001379631.1

HGVSc / HGVSpc.4687C>Tp.Arg1563Cys

Exon rankExon 43 of 49

missense

Prot: NP_001366560.1

KIF1A NM_001379642.1

HGVSc / HGVSpc.4612C>Tp.Arg1538Cys

Exon rankExon 43 of 49

missense

Prot: NP_001366571.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KIF1A ENST00000498729.9	TSL:5MANE Select	c.4612C>T p.Arg1538Cys	missense	Exon 43 of 49	Prot: ENSP00000438388.1 UniProt:
	KIF1A ENST00000460788.5	TSL:1	n.1169C>T	non_coding_transcript_exon	Exon 3 of 9	Prot:
	KIF1A ENST00000492812.6	TSL:1	n.3195C>T	non_coding_transcript_exon	Exon 10 of 16	Prot:

KIF1A ENST00000498729.9

TSL:5MANE Select

HGVSc / HGVSpc.4612C>Tp.Arg1538Cys

Exon rankExon 43 of 49

missense

Prot: ENSP00000438388.1UniProt: Q12756-3

KIF1A ENST00000460788.5

TSL:1

HGVSc / HGVSpn.1169C>T

Exon rankExon 3 of 9

non_coding_transcript_exon

Prot:

KIF1A ENST00000492812.6

TSL:1

HGVSc / HGVSpn.3195C>T

Exon rankExon 10 of 16

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00139	AC:212	Hom:0	AN:152124	Cov:33
GnomAD2 exomes	AF: 0.000552	AC:83	Hom:	AN:150482	Cov:
GnomAD4 exome	AF: 0.000232	AC:324	Hom:0	AN:1395758	Cov:32
GnomAD4 genome	AF: 0.00141	AC:214	Hom:0	AN:152242	Cov:33
TOPMed (Bravo)	AF: 0.00179	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00141	AC:93	Hom:0	AN:65888	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00128	AC:3	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00188	AC:21	Hom:	AN:11174	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28408	0.00	0	28844
Epi25(Epilepsy)	0.000215	9	41958	0.000449	30	66852
SCHEMA(Schizophrenia)	0.000818	86	105190	0.000874	152	173836

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 30 (1)
-	-	1	KIF1A-related disorder (1)
-	-	1	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.28	N
GPN-Star LLR	N/A	-5.5
GPN-Star score	N/A	5.5
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.80	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Benign	0.49	N
PhyloP100	Benign	1.7
popEVE	Benign	-3.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.076
Sift	Benign	0.078	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.068
VESM-3B	Benign	-3.9

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200184619;

hg19: chr2-241661926;

COSMIC: COSV107338420;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar