chr14-23383327-G-C

Variant names:

• chr14-23383327-G-C
• rs200509899
• NM_002471.4:c.5566-7C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002471.4(MYH6):​c.5566-7C>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 0.00000121 in 823,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• Publications: 0 publications found

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.5566-7C>G		splice_region intron	N/A	NP_002462.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.5566-7C>G		splice_region intron	N/A	ENSP00000386041.3
	MYH6	ENST00000651452.1		n.786C>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000121 AC: 1 AN: 823812 Hom.: 0 Cov.: 25 AF XY: 0.00000236 AC XY: 1 AN XY: 424188

⚠️ 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: 19826

American (AMR) AF: 0.00 AC: 0 AN: 36240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17982

East Asian (EAS) AF: 0.00 AC: 0 AN: 25846

South Asian (SAS) AF: 0.00 AC: 0 AN: 70332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2596

European-Non Finnish (NFE) AF: 0.00000171 AC: 1 AN: 583244

Other (OTH) AF: 0.00 AC: 0 AN: 34764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	22
DANN	Benign	0.66
PhyloP100		-0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -1
DS_AL_spliceai		0.84		Position offset: -7

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

Other links and lift over

dbSNP: rs200509899; hg19: chr14-23852536;