2-240774229-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBA1

The NM_001244008.2(KIF1A):c.991T>C(p.Leu331Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.366 in 1,608,610 control chromosomes in the GnomAD database, including 114,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16938 hom., cov: 33)

Exomes 𝑓: 0.36 ( 97144 hom. )

Consequence

KIF1A
NM_001244008.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.67

Publications

19 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.266).

BP6

Variant 2-240774229-A-G is Benign according to our data. Variant chr2-240774229-A-G is described in ClinVar as Benign. ClinVar VariationId is 129396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 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.991T>C	p.Leu331Leu	synonymous	Exon 12 of 49	NP_001230937.1	Q12756-3
KIF1A	NM_001379631.1		c.991T>C	p.Leu331Leu	synonymous	Exon 12 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.991T>C	p.Leu331Leu	synonymous	Exon 12 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.991T>C	p.Leu331Leu	synonymous	Exon 12 of 49	ENSP00000438388.1	Q12756-3
KIF1A	ENST00000675932.2		c.991T>C	p.Leu331Leu	synonymous	Exon 12 of 49	ENSP00000502786.2	A0A6Q8PHQ5
KIF1A	ENST00000675314.2		c.1120T>C	p.Leu374Leu	synonymous	Exon 13 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes

AF:

0.447

AC:

67904

AN:

151984

Hom.:

16921

Cov.:

show subpopulations

Gnomad AFR

AF:

0.677

Gnomad AMI

AF:

0.417

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.315

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.349

Gnomad OTH

AF:

0.420

GnomAD2 exomes

AF:

0.374

AC:

92453

AN:

247338

AF XY:

0.365

show subpopulations

Gnomad AFR exome

AF:

0.682

Gnomad AMR exome

AF:

0.304

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.588

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.380

GnomAD4 exome

AF:

0.358

AC:

520723

AN:

1456508

Hom.:

97144

Cov.:

AF XY:

0.355

AC XY:

257111

AN XY:

724676

show subpopulations

African (AFR)

AF:

0.693

AC:

23127

AN:

33386

American (AMR)

AF:

0.313

AC:

13960

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

8089

AN:

26014

East Asian (EAS)

AF:

0.604

AC:

23905

AN:

39582

South Asian (SAS)

AF:

0.310

AC:

26600

AN:

85848

European-Finnish (FIN)

AF:

0.322

AC:

17173

AN:

53278

Middle Eastern (MID)

AF:

0.361

AC:

2075

AN:

5750

European-Non Finnish (NFE)

AF:

0.346

AC:

382971

AN:

1107926

Other (OTH)

AF:

0.379

AC:

22823

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

14361

28722

43084

57445

71806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12412

24824

37236

49648

62060

<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:

0.447

AC:

67953

AN:

152102

Hom.:

16938

Cov.:

AF XY:

0.443

AC XY:

32934

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.676

AC:

28065

AN:

41488

American (AMR)

AF:

0.372

AC:

5684

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1107

AN:

3470

East Asian (EAS)

AF:

0.605

AC:

3129

AN:

5170

South Asian (SAS)

AF:

0.327

AC:

1575

AN:

4822

European-Finnish (FIN)

AF:

0.315

AC:

3336

AN:

10586

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.349

AC:

23695

AN:

67962

Other (OTH)

AF:

0.415

AC:

875

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1765

3530

5296

7061

8826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.385

Hom.:

7805

Bravo

AF:

0.461

Asia WGS

AF:

0.462

AC:

1610

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

6.7

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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