rs193922713

Positions:

• chr20-31824366-G-A
• chr20-31824366-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_033118.4(MYLK2):​c.972+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,603,684 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (5 hom.)
• Consequence: MYLK2 NM_033118.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.333

Genes affected

MYLK2 (HGNC:16243): (myosin light chain kinase 2) This gene encodes a myosin light chain kinase, a calcium/calmodulin dependent enzyme, that is exclusively expressed in adult skeletal muscle. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-31824366-G-A is Benign according to our data. Variant chr20-31824366-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-31824366-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 41 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.972+14G>A		intron_variant		ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.972+14G>A		intron_variant		1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.972+14G>A		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000721 AC: 167 AN: 231494 Hom.: 0 AF XY: 0.000846 AC XY: 106 AN XY: 125344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.000688

GnomAD4 exome AF: 0.000404 AC: 587 AN: 1451334 Hom.: 5 Cov.: 33 AF XY: 0.000508 AC XY: 366 AN XY: 721078

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000683

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00363

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.000417

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000181

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 21, 2013	972+14G>A in intron 6 of MYLK2: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It ha s been identified in 5/8600 European American chromosomes by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs193922713). 972+14G >A in intron 6 of MYLK2 (rs193922713; allele frequency = 5/8600) ** -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2018	Variant summary: MYLK2 c.972+14G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 257916 control chromosomes, predominantly at a frequency of 0.0041 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 164 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.972+14G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs193922713; hg19: chr20-30412169;