Genetic Variant XR_001739733.2:n.8182G>T (chr2-148875136-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The XR_001739733.2(KIF5C-AS1):n.8182G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 108,672 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 26 hom., cov: 29)

Exomes 𝑓: 0.014 ( 0 hom. )

Consequence

KIF5C-AS1
XR_001739733.2 non_coding_transcript_exon

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.378

Publications

0 publications found

Variant links:

Genes affected

KIF5C-AS1 (HGNC:40325): (KIF5C antisense RNA 1)

KIF5C-AS1 links:

KIF5C (HGNC:6325): (kinesin family member 5C) The protein encoded by this gene is a kinesin heavy chain subunit involved in the transport of cargo within the central nervous system. The encoded protein, which acts as a tetramer by associating with another heavy chain and two light chains, interacts with protein kinase CK2. Mutations in this gene have been associated with complex cortical dysplasia with other brain malformations-2. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Jul 2015]

KIF5C Gene-Disease associations (from GenCC):

complex cortical dysplasia with other brain malformations 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen

KIF5C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 2-148875136-C-A is Benign according to our data. Variant chr2-148875136-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 679867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0203 (2180/107504) while in subpopulation AMR AF = 0.0307 (247/8040). AF 95% confidence interval is 0.0276. There are 26 homozygotes in GnomAd4. There are 1042 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000435030.6. 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
	KIF5C	NM_004522.3	MANE Select	c.-482C>A		upstream_gene	N/A	NP_004513.1	O60282-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KIF5C-AS1	ENST00000601658.5	TSL:5	n.676+2090G>T	intron	N/A
KIF5C	ENST00000435030.6	TSL:1 MANE Select	c.-482C>A	upstream_gene	N/A	ENSP00000393379.1	O60282-1
KIF5C	ENST00000677891.1		c.-482C>A	upstream_gene	N/A	ENSP00000503013.1	O60282-1

Frequencies

GnomAD3 genomes

AF:

0.0203

AC:

2180

AN:

107476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00596

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0563

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00808

Gnomad FIN

AF:

0.0309

Gnomad MID

AF:

0.0704

Gnomad NFE

AF:

0.0245

Gnomad OTH

AF:

0.0319

GnomAD4 exome

AF:

0.0137

AC:

AN:

1168

Hom.:

AF XY:

0.0149

AC XY:

AN XY:

672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0625

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0148

AC:

AN:

876

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0203

AC:

2180

AN:

107504

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1042

AN XY:

49960

show subpopulations

African (AFR)

AF:

0.00599

AC:

168

AN:

28062

American (AMR)

AF:

0.0307

AC:

247

AN:

8040

Ashkenazi Jewish (ASJ)

AF:

0.0563

AC:

171

AN:

3038

East Asian (EAS)

AF:

0.00

AC:

AN:

3166

South Asian (SAS)

AF:

0.00809

AC:

AN:

2842

European-Finnish (FIN)

AF:

0.0309

AC:

119

AN:

3846

Middle Eastern (MID)

AF:

0.0682

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0245

AC:

1376

AN:

56184

Other (OTH)

AF:

0.0316

AC:

AN:

1424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

109

219

328

438

547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.1

(source)

DANN

Benign

0.89

PhyloP100

0.38

PromoterAI

0.044

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over