12-110913195-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000432.4(MYL2):c.353+51C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,286 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 33)
  • Exomes 𝑓: 0.014 (217 hom.)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.211

Genes affected

MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-110913195-G-T is Benign according to our data. Variant chr12-110913195-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 671321.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-110913195-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1848/151498) while in subpopulation NFE AF= 0.0153 (1041/68008). AF 95% confidence interval is 0.0145. There are 14 homozygotes in gnomad4. There are 1002 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1847 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.353+51C>A		intron_variant		ENST00000228841.15
MYL2	NM_001406745.1	c.311+51C>A		intron_variant
MYL2	NM_001406916.1	c.296+51C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.353+51C>A		intron_variant		1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.311+51C>A		intron_variant		3
MYL2	ENST00000663220.1	c.296+51C>A		intron_variant
MYL2	ENST00000549029.1	n.235C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1847 AN: 151378 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00209

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0136 AC: 3387 AN: 248922 Hom.: 51 AF XY: 0.0138 AC XY: 1856 AN XY: 134502

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.00770

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00616

Gnomad FIN exome AF: 0.0486

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0143 AC: 20939 AN: 1461788 Hom.: 217 Cov.: 38 AF XY: 0.0141 AC XY: 10278 AN XY: 727192

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00803

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00630

Gnomad4 FIN exome AF: 0.0429

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0122 AC: 1848 AN: 151498 Hom.: 14 Cov.: 33 AF XY: 0.0135 AC XY: 1002 AN XY: 74082

Gnomad4 AFR AF: 0.00208

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0457

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00185 Hom.: 2827

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.48
Dann	Benign	0.65

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: rs2233260; hg19: chr12-111350999;