rs878988727

Variant names:

• chr2-240757426-C-CTCCTCCTCCTCA
• rs878988727
• NM_001244008.2:c.2750_2751insTGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001244008.2(KIF1A):​c.2750_2751insTGAGGAGGAGGA​(p.Glu916_Glu917insAspGluGluGlu) variant causes a disruptive inframe insertion change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.77
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2750_2751insTGAGGAGGAGGA	p.Glu916_Glu917insAspGluGluGlu	disruptive_inframe_insertion	Exon 27 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2750_2751insTGAGGAGGAGGA	p.Glu916_Glu917insAspGluGluGlu	disruptive_inframe_insertion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 1 AN: 22392 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000771

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000764 AC: 1 AN: 130910 AF XY: 0.0000142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000997

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000168 AC: 36 AN: 213710 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 17 AN XY: 105398

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 578

American (AMR) AF: 0.00 AC: 0 AN: 7184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2344

East Asian (EAS) AF: 0.00 AC: 0 AN: 2116

South Asian (SAS) AF: 0.00 AC: 0 AN: 16844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 880

European-Non Finnish (NFE) AF: 0.000206 AC: 35 AN: 169682

Other (OTH) AF: 0.000129 AC: 1 AN: 7750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000447 AC: 1 AN: 22392 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11324

African (AFR) AF: 0.00 AC: 0 AN: 830

American (AMR) AF: 0.00 AC: 0 AN: 3300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 474

East Asian (EAS) AF: 0.00 AC: 0 AN: 454

South Asian (SAS) AF: 0.00 AC: 0 AN: 1592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.0000771 AC: 1 AN: 12962

Other (OTH) AF: 0.00 AC: 0 AN: 276

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

-

Paris Brain Institute, Inserm - ICM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 23, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=87/13	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs878988727; hg19: chr2-241696843;