2-240746169-G-A

Variant names:

• chr2-240746169-G-A
• rs73102625
• NM_001244008.2:c.3072C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001244008.2(KIF1A):​c.3072C>T​(p.Ser1024Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 1,562,738 control chromosomes in the GnomAD database, including 2,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1024S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.059 (289 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2298 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.23
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.055).
• BP6: Variant 2-240746169-G-A is Benign according to our data. Variant chr2-240746169-G-A is described in ClinVar as Benign. ClinVar VariationId is 129389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0727 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3072C>T	p.Ser1024Ser	synonymous	Exon 30 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3147C>T	p.Ser1049Ser	synonymous	Exon 30 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3045C>T	p.Ser1015Ser	synonymous	Exon 29 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.3072C>T	p.Ser1024Ser	synonymous	Exon 30 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.3072C>T	p.Ser1024Ser	synonymous	Exon 30 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.3201C>T	p.Ser1067Ser	synonymous	Exon 31 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.0584 AC: 8891 AN: 152132 Hom.: 283 Cov.: 33

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.00733

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0475 AC: 8062 AN: 169706 AF XY: 0.0463

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0555

Gnomad EAS exome AF: 0.00562

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0606

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0560 AC: 79004 AN: 1410488 Hom.: 2298 Cov.: 33 AF XY: 0.0556 AC XY: 38761 AN XY: 696896

African (AFR) AF: 0.0751 AC: 2417 AN: 32164

American (AMR) AF: 0.0307 AC: 1137 AN: 37052

Ashkenazi Jewish (ASJ) AF: 0.0564 AC: 1428 AN: 25298

East Asian (EAS) AF: 0.00406 AC: 149 AN: 36660

South Asian (SAS) AF: 0.0337 AC: 2692 AN: 79928

European-Finnish (FIN) AF: 0.0487 AC: 2390 AN: 49100

Middle Eastern (MID) AF: 0.0505 AC: 288 AN: 5708

European-Non Finnish (NFE) AF: 0.0601 AC: 65247 AN: 1086088

Other (OTH) AF: 0.0557 AC: 3256 AN: 58490

GnomAD4 genome AF: 0.0585 AC: 8910 AN: 152250 Hom.: 289 Cov.: 33 AF XY: 0.0567 AC XY: 4221 AN XY: 74438

African (AFR) AF: 0.0749 AC: 3110 AN: 41546

American (AMR) AF: 0.0374 AC: 572 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.00715 AC: 37 AN: 5172

South Asian (SAS) AF: 0.0302 AC: 146 AN: 4828

European-Finnish (FIN) AF: 0.0498 AC: 529 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0605 AC: 4113 AN: 67992

Other (OTH) AF: 0.0483 AC: 102 AN: 2110

Alfa AF: 0.0400 Hom.: 33

Bravo AF: 0.0594

Asia WGS AF: 0.0290 AC: 105 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	KIF1A-related disorder (1)
-	-	1	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-6.2
PromoterAI		0.0056	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs73102625; hg19: chr2-241685586;