rs144520412

Variant names:

• chr2-240740071-G-A
• rs144520412
• NM_001244008.2:c.3888C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240740071-G-A
• chr2-240740071-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001244008.2(KIF1A):​c.3888C>T​(p.Arg1296Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,585,678 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1296R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -2.30
• 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 -9 ACMG points.

• BP6: Variant 2-240740071-G-A is Benign according to our data. Variant chr2-240740071-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 335266.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0021 (319/152250) while in subpopulation AMR AF = 0.00503 (77/15298). AF 95% confidence interval is 0.00413. There are 0 homozygotes in GnomAd4. There are 157 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.3888C>T	p.Arg1296Arg	synonymous	Exon 37 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3963C>T	p.Arg1321Arg	synonymous	Exon 37 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3861C>T	p.Arg1287Arg	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.3888C>T	p.Arg1296Arg	synonymous	Exon 37 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000492812.6	TSL:1	n.1050C>T		non_coding_transcript_exon	Exon 5 of 16
	KIF1A	ENST00000675932.2		c.3888C>T	p.Arg1296Arg	synonymous	Exon 37 of 49	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00229 AC: 472 AN: 206502 AF XY: 0.00235

Gnomad AFR exome AF: 0.000175

Gnomad AMR exome AF: 0.00603

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.000274

Gnomad FIN exome AF: 0.0000528

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00278 AC: 3981 AN: 1433428 Hom.: 11 Cov.: 32 AF XY: 0.00270 AC XY: 1915 AN XY: 710230

African (AFR) AF: 0.000399 AC: 13 AN: 32592

American (AMR) AF: 0.00585 AC: 240 AN: 41018

Ashkenazi Jewish (ASJ) AF: 0.0000780 AC: 2 AN: 25656

East Asian (EAS) AF: 0.000846 AC: 32 AN: 37838

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81694

European-Finnish (FIN) AF: 0.000137 AC: 7 AN: 51162

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5746

European-Non Finnish (NFE) AF: 0.00320 AC: 3517 AN: 1098328

Other (OTH) AF: 0.00278 AC: 165 AN: 59394

GnomAD4 genome AF: 0.00210 AC: 319 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74448

African (AFR) AF: 0.000626 AC: 26 AN: 41536

American (AMR) AF: 0.00503 AC: 77 AN: 15298

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

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68018

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	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	-0.66
CADD	Benign	8.7
DANN	Benign	0.71
PhyloP100		-2.3
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144520412; hg19: chr2-241679488;