Genetic Variant KIF1A:p.Pro1381Pro (chr2-240725384-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001244008.2(KIF1A):c.4143G>A(p.Pro1381Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,612,268 control chromosomes in the GnomAD database, including 3,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 376 hom., cov: 32)

Exomes 𝑓: 0.015 ( 2717 hom. )

Consequence

KIF1A
NM_001244008.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -5.14

Publications

8 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, G2P, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuropathy, hereditary sensory, type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.053).

BP6

Variant 2-240725384-C-T is Benign according to our data. Variant chr2-240725384-C-T is described in ClinVar as Benign. ClinVar VariationId is 129393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1A	NM_001244008.2	MANE Select	c.4143G>A	p.Pro1381Pro	synonymous	Exon 40 of 49	NP_001230937.1	Q12756-3
KIF1A	NM_001379631.1		c.4218G>A	p.Pro1406Pro	synonymous	Exon 40 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.4143G>A	p.Pro1381Pro	synonymous	Exon 40 of 49	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.4143G>A	p.Pro1381Pro	synonymous	Exon 40 of 49	ENSP00000438388.1	Q12756-3
KIF1A	ENST00000492812.6	TSL:1	n.2726G>A		non_coding_transcript_exon	Exon 7 of 16
KIF1A	ENST00000675932.2		c.4143G>A	p.Pro1381Pro	synonymous	Exon 40 of 49	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3808

AN:

152168

Hom.:

374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0929

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.306

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.0273

GnomAD2 exomes

AF:

0.0392

AC:

9686

AN:

246782

AF XY:

0.0339

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.292

Gnomad FIN exome

AF:

0.00429

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.0273

GnomAD4 exome

AF:

0.0148

AC:

21641

AN:

1459982

Hom.:

2717

Cov.:

AF XY:

0.0141

AC XY:

10234

AN XY:

726232

show subpopulations

African (AFR)

AF:

0.0130

AC:

435

AN:

33474

American (AMR)

AF:

0.105

AC:

4663

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26106

East Asian (EAS)

AF:

0.337

AC:

13364

AN:

39672

South Asian (SAS)

AF:

0.00732

AC:

631

AN:

86188

European-Finnish (FIN)

AF:

0.00378

AC:

197

AN:

52134

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000718

AC:

798

AN:

1111700

Other (OTH)

AF:

0.0243

AC:

1464

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

851

1702

2553

3404

4255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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

AF:

0.0251

AC:

3823

AN:

152286

Hom.:

376

Cov.:

AF XY:

0.0281

AC XY:

2096

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0138

AC:

574

AN:

41576

American (AMR)

AF:

0.0934

AC:

1430

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.305

AC:

1573

AN:

5150

South Asian (SAS)

AF:

0.0112

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

68018

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00904

Hom.:

120

Bravo

AF:

0.0303

Asia WGS

AF:

0.123

AC:

425

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 30 (1)

Inborn genetic diseases (1)

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.91

(source)

DANN

Benign

0.56

PhyloP100

-5.1

Mutation Taster

=98/2

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over