7-74097072-C-G

Variant names:

• chr7-74097072-C-G
• rs116341069
• NM_002314.4:c.292-8C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002314.4(LIMK1):​c.292-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,600,782 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: LIMK1 NM_002314.4 splice_region, intron
• Scores: Splicing: ADA: 0.001296
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.60

Genes affected

LIMK1 (HGNC:6613): (LIM domain kinase 1) There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs and a C-terminal protein kinase domain. LIMK1 is a serine/threonine kinase that regulates actin polymerization via phosphorylation and inactivation of the actin binding factor cofilin. This protein is ubiquitously expressed during development and plays a role in many cellular processes associated with cytoskeletal structure. This protein also stimulates axon growth and may play a role in brain development. LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Feb 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-74097072-C-G is Benign according to our data. Variant chr7-74097072-C-G is described in ClinVar as [Benign]. Clinvar id is 709429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1574/152272) while in subpopulation AFR AF = 0.0367 (1527/41560). AF 95% confidence interval is 0.0352. There are 41 homozygotes in GnomAd4. There are 755 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIMK1	NM_002314.4	c.292-8C>G		splice_region_variant, intron_variant	Intron 3 of 15	ENST00000336180.7	NP_002305.1
LIMK1	NM_001204426.2	c.190-8C>G		splice_region_variant, intron_variant	Intron 2 of 14		NP_001191355.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIMK1	ENST00000336180.7	c.292-8C>G		splice_region_variant, intron_variant	Intron 3 of 15	1	NM_002314.4	ENSP00000336740.2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1575 AN: 152154 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00263 AC: 647 AN: 245692 AF XY: 0.00201

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.00101 AC: 1462 AN: 1448510 Hom.: 25 Cov.: 29 AF XY: 0.000900 AC XY: 649 AN XY: 720810

Gnomad4 AFR exome AF: 0.0387 AC: 1290 AN: 33298

Gnomad4 AMR exome AF: 0.00122 AC: 54 AN: 44356

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25670

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39622

Gnomad4 SAS exome AF: 0.000153 AC: 13 AN: 85194

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53124

Gnomad4 NFE exome AF: 0.00000545 AC: 6 AN: 1101712

Gnomad4 Remaining exome AF: 0.00162 AC: 97 AN: 59864

GnomAD4 genome AF: 0.0103 AC: 1574 AN: 152272 Hom.: 41 Cov.: 32 AF XY: 0.0101 AC XY: 755 AN XY: 74470

Gnomad4 AFR AF: 0.0367 AC: 0.0367421 AN: 0.0367421

Gnomad4 AMR AF: 0.00229 AC: 0.00229088 AN: 0.00229088

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000622 AC: 0.000621891 AN: 0.000621891

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294057 AN: 0.0000294057

Gnomad4 OTH AF: 0.00331 AC: 0.00330813 AN: 0.00330813

Alfa AF: 0.000815 Hom.: 1

Bravo AF: 0.0115

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LIMK1-related disorder Benign:1

Jun 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.45
DANN	Benign	0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.064
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

Publications

LitVar

Other links and lift over

dbSNP: rs116341069; hg19: chr7-73511402;