2-240720970-G-T

Variant names:

• chr2-240720970-G-T
• rs76974316
• NM_001244008.2:c.4812C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.4812C>A​(p.Thr1604Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,605,664 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1604T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (23 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.69
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-240720970-G-T is Benign according to our data. Variant chr2-240720970-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00821 (1251/152316) while in subpopulation AFR AF = 0.022 (914/41576). AF 95% confidence interval is 0.0208. There are 15 homozygotes in GnomAd4. There are 619 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.4812C>A	p.Thr1604Thr	synonymous	Exon 45 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.4887C>A	p.Thr1629Thr	synonymous	Exon 45 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4812C>A	p.Thr1604Thr	synonymous	Exon 45 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.4812C>A	p.Thr1604Thr	synonymous	Exon 45 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000460788.5	TSL:1	n.1369C>A		non_coding_transcript_exon	Exon 5 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3395C>A		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152198 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00353 AC: 827 AN: 234084 AF XY: 0.00328

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00947

Gnomad EAS exome AF: 0.0000584

Gnomad FIN exome AF: 0.0000501

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00198 AC: 2879 AN: 1453348 Hom.: 23 Cov.: 31 AF XY: 0.00191 AC XY: 1379 AN XY: 722056

African (AFR) AF: 0.0250 AC: 836 AN: 33382

American (AMR) AF: 0.00636 AC: 278 AN: 43678

Ashkenazi Jewish (ASJ) AF: 0.00916 AC: 238 AN: 25974

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39396

South Asian (SAS) AF: 0.000130 AC: 11 AN: 84664

European-Finnish (FIN) AF: 0.0000386 AC: 2 AN: 51798

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5744

European-Non Finnish (NFE) AF: 0.00105 AC: 1162 AN: 1108618

Other (OTH) AF: 0.00481 AC: 289 AN: 60094

GnomAD4 genome AF: 0.00821 AC: 1251 AN: 152316 Hom.: 15 Cov.: 33 AF XY: 0.00831 AC XY: 619 AN XY: 74490

African (AFR) AF: 0.0220 AC: 914 AN: 41576

American (AMR) AF: 0.0104 AC: 159 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68024

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00420 Hom.: 3

Bravo AF: 0.0100

Asia WGS AF: 0.00173 AC: 6 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	1.4
DANN	Benign	0.62
PhyloP100		-1.7
PromoterAI		-0.0062	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76974316; hg19: chr2-241660387;