14-23389062-A-G

Variant names:

• chr14-23389062-A-G
• rs535111647
• NM_002471.4:c.3979-7T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000405093.9(MYH6):​c.3979-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.015 (7 hom., cov: 26)
  • Exomes 𝑓: 0.016 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 ENST00000405093.9 splice_region, intron
• Scores: Splicing: ADA: 0.00006140
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.588
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-23389062-A-G is Benign according to our data. Variant chr14-23389062-A-G is described in ClinVar as Benign. ClinVar VariationId is 239170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000405093.9. 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.3979-7T>C		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.3979-7T>C		splice_region intron	N/A	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 1752 AN: 115424 Hom.: 7 Cov.: 26

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0133

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0120

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00775

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0140

GnomAD2 exomes AF: 0.0589 AC: 8229 AN: 139674 AF XY: 0.0582

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.0708

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0668

Gnomad OTH exome AF: 0.0588

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0162 AC: 17102 AN: 1053674 Hom.: 5 Cov.: 27 AF XY: 0.0180 AC XY: 9439 AN XY: 524690

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0164 AC: 498 AN: 30344

American (AMR) AF: 0.0685 AC: 2000 AN: 29182

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 425 AN: 19270

East Asian (EAS) AF: 0.0209 AC: 575 AN: 27516

South Asian (SAS) AF: 0.0465 AC: 2992 AN: 64298

European-Finnish (FIN) AF: 0.0434 AC: 1505 AN: 34694

Middle Eastern (MID) AF: 0.0115 AC: 48 AN: 4176

European-Non Finnish (NFE) AF: 0.0103 AC: 8266 AN: 799326

Other (OTH) AF: 0.0177 AC: 793 AN: 44868

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0152 AC: 1751 AN: 115534 Hom.: 7 Cov.: 26 AF XY: 0.0135 AC XY: 767 AN XY: 56790

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0155 AC: 601 AN: 38874

American (AMR) AF: 0.0103 AC: 116 AN: 11274

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 31 AN: 2588

East Asian (EAS) AF: 0.0145 AC: 44 AN: 3026

South Asian (SAS) AF: 0.00992 AC: 34 AN: 3426

European-Finnish (FIN) AF: 0.0148 AC: 105 AN: 7074

Middle Eastern (MID) AF: 0.00826 AC: 2 AN: 242

European-Non Finnish (NFE) AF: 0.0168 AC: 787 AN: 46764

Other (OTH) AF: 0.0138 AC: 22 AN: 1590

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.5
DANN	Benign	0.76
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs535111647; hg19: chr14-23858271;