2-240737359-G-A

Variant names:

• chr2-240737359-G-A
• rs10174559
• NM_001244008.2:c.3902-191C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.3902-191C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 531,326 control chromosomes in the GnomAD database, including 24,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10637 hom., cov: 30)
  • Exomes 𝑓: 0.26 (13985 hom.)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42
• 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, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-240737359-G-A is Benign according to our data. Variant chr2-240737359-G-A is described in ClinVar as Benign. ClinVar VariationId is 1231571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3902-191C>T		intron	N/A	NP_001230937.1
	KIF1A	NM_001379631.1		c.3977-191C>T		intron	N/A	NP_001366560.1
	KIF1A	NM_001379642.1		c.3875-191C>T		intron	N/A	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3902-191C>T		intron	N/A	ENSP00000438388.1
	KIF1A	ENST00000492812.6	TSL:1	n.1064-191C>T		intron	N/A
	KIF1A	ENST00000494452.1	TSL:2	n.184C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51750 AN: 151742 Hom.: 10616 Cov.: 30

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.258 AC: 98041 AN: 379466 Hom.: 13985 Cov.: 2 AF XY: 0.253 AC XY: 50301 AN XY: 198796

African (AFR) AF: 0.583 AC: 6645 AN: 11392

American (AMR) AF: 0.289 AC: 5496 AN: 19050

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 3253 AN: 11776

East Asian (EAS) AF: 0.396 AC: 10853 AN: 27392

South Asian (SAS) AF: 0.189 AC: 7625 AN: 40304

European-Finnish (FIN) AF: 0.210 AC: 5233 AN: 24916

Middle Eastern (MID) AF: 0.282 AC: 468 AN: 1662

European-Non Finnish (NFE) AF: 0.237 AC: 52260 AN: 220960

Other (OTH) AF: 0.282 AC: 6208 AN: 22014

GnomAD4 genome AF: 0.341 AC: 51814 AN: 151860 Hom.: 10637 Cov.: 30 AF XY: 0.337 AC XY: 25009 AN XY: 74204

African (AFR) AF: 0.583 AC: 24130 AN: 41394

American (AMR) AF: 0.314 AC: 4790 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 974 AN: 3460

East Asian (EAS) AF: 0.381 AC: 1949 AN: 5118

South Asian (SAS) AF: 0.200 AC: 961 AN: 4810

European-Finnish (FIN) AF: 0.197 AC: 2077 AN: 10558

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.235 AC: 15969 AN: 67932

Other (OTH) AF: 0.330 AC: 696 AN: 2108

Alfa AF: 0.272 Hom.: 7704

Bravo AF: 0.362

Asia WGS AF: 0.290 AC: 1011 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.074
DANN	Benign	0.49
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10174559; hg19: chr2-241676776;