dbSNP rs7594776: KIF1A:c.184-10C>T (chr2-240788240-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001244008.2(KIF1A):c.184-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,612,942 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 23 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 21 hom. )

Consequence

KIF1A
NM_001244008.2 intron

Scores

Splicing: ADA: 0.00001958

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.175

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 2-240788240-G-A is Benign according to our data. Variant chr2-240788240-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00812 (1237/152310) while in subpopulation AFR AF = 0.0287 (1193/41564). AF 95% confidence interval is 0.0273. There are 23 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR,AD gene

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	Effect	Exon Rank	Protein	UniProt
KIF1A	NM_001244008.2	MANE Select	c.184-10C>T	intron	N/A	NP_001230937.1	Q12756-3
KIF1A	NM_001379631.1		c.184-10C>T	intron	N/A	NP_001366560.1
KIF1A	NM_001379642.1		c.184-10C>T	intron	N/A	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.184-10C>T	intron	N/A	ENSP00000438388.1	Q12756-3
KIF1A	ENST00000675932.2		c.184-10C>T	intron	N/A	ENSP00000502786.2	A0A6Q8PHQ5
KIF1A	ENST00000675314.2		c.313-10C>T	intron	N/A	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes

AF:

0.00803

AC:

1222

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0284

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00219

AC:

543

AN:

247414

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.0308

Gnomad AMR exome

AF:

0.000843

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000715

Gnomad OTH exome

AF:

0.000999

GnomAD4 exome

AF:

0.000861

AC:

1258

AN:

1460632

Hom.:

Cov.:

AF XY:

0.000754

AC XY:

548

AN XY:

726540

show subpopulations

African (AFR)

AF:

0.0304

AC:

1018

AN:

33450

American (AMR)

AF:

0.000985

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000732

AC:

AN:

86070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111394

Other (OTH)

AF:

0.00144

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00812

AC:

1237

AN:

152310

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0287

AC:

1193

AN:

41564

American (AMR)

AF:

0.00144

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00441

Hom.:

Bravo

AF:

0.00894

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 30 (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

-0.89

CADD

Benign

0.030

(source)

DANN

Benign

0.73

PhyloP100

-0.17

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.0

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