2-240758462-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001244008.2(KIF1A):c.2480G>A(p.Arg827His) variant causes a missense change. The variant allele was found at a frequency of 0.00000825 in 1,455,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R827C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.80

Publications

3 publications found

Variant links:

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, 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
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

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 2-240758462-C-T is Benign according to our data. Variant chr2-240758462-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464221.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.2480G>A	p.Arg827His	missense_variant	Exon 26 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.2480G>A	p.Arg827His	missense_variant	Exon 26 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000837

AC:

AN:

238892

AF XY:

0.0000154

show subpopulations

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:

0.00000926

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000825

AC:

AN:

1455350

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

723540

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33302

American (AMR)

AF:

0.00

AC:

AN:

43962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000812

AC:

AN:

1108902

Other (OTH)

AF:

0.00

AC:

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9

Benign:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.0077

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;.;.;.;.;.;.;T;.;.;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.43

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.5

L;.;.;.;.;.;.;L;.;.;.;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

.;D;N;.;.;.;.;.;.;.;.;.;D

REVEL

Uncertain

0.38

Sift

Benign

0.039

.;D;T;.;.;.;.;.;.;.;.;.;T

Sift4G

Benign

0.31

.;T;T;.;.;.;.;.;.;.;.;.;.

Polyphen

0.20

B;.;.;.;.;.;.;B;.;.;.;.;P

Vest4

0.44, 0.44

MutPred

0.41

Gain of disorder (P = 0.1053);.;Gain of disorder (P = 0.1053);.;.;Gain of disorder (P = 0.1053);Gain of disorder (P = 0.1053);Gain of disorder (P = 0.1053);Gain of disorder (P = 0.1053);.;Gain of disorder (P = 0.1053);.;.;

MVP

0.64

MPC

0.80

ClinPred

0.82

GERP RS

5.3

Varity_R

0.15

gMVP

0.48

Mutation Taster

=35/65

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over