rs184931664

Variant names:

• chr2-240740107-A-G
• rs184931664
• NM_001244008.2:c.3852T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.3852T>C​(p.His1284His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,590,346 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (5 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0250
• Publications: 0 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, 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

ACMG classification

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

• BP6: Variant 2-240740107-A-G is Benign according to our data. Variant chr2-240740107-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00654 (996/152188) while in subpopulation AFR AF = 0.0218 (906/41484). AF 95% confidence interval is 0.0207. There are 8 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3852T>C	p.His1284His	synonymous	Exon 37 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3927T>C	p.His1309His	synonymous	Exon 37 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3825T>C	p.His1275His	synonymous	Exon 36 of 49	NP_001366571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3852T>C	p.His1284His	synonymous	Exon 37 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000492812.6	TSL:1	n.1014T>C		non_coding_transcript_exon	Exon 5 of 16
	KIF1A	ENST00000675932.2		c.3852T>C	p.His1284His	synonymous	Exon 37 of 49	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 989 AN: 152070 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00146 AC: 309 AN: 211310 AF XY: 0.00119

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.000903 AC: 1298 AN: 1438158 Hom.: 5 Cov.: 32 AF XY: 0.000846 AC XY: 603 AN XY: 713072

African (AFR) AF: 0.0203 AC: 665 AN: 32822

American (AMR) AF: 0.00174 AC: 72 AN: 41322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25758

East Asian (EAS) AF: 0.00 AC: 0 AN: 38226

South Asian (SAS) AF: 0.0000485 AC: 4 AN: 82452

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51198

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5746

European-Non Finnish (NFE) AF: 0.000370 AC: 407 AN: 1101080

Other (OTH) AF: 0.00223 AC: 133 AN: 59554

GnomAD4 genome AF: 0.00654 AC: 996 AN: 152188 Hom.: 8 Cov.: 32 AF XY: 0.00617 AC XY: 459 AN XY: 74434

African (AFR) AF: 0.0218 AC: 906 AN: 41484

American (AMR) AF: 0.00301 AC: 46 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00356 Hom.: 3

Bravo AF: 0.00759

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	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	-0.81
CADD	Benign	0.055
DANN	Benign	0.34
PhyloP100		-0.025
Mutation Taster		=100/0	polymorphism

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: rs184931664; hg19: chr2-241679524;