14-23389062-AGGG-AGGGGG

Variant names:

• chr14-23389062-A-AGG
• rs193922652
• NM_002471.4:c.3979-9_3979-8dupCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_002471.4(MYH6):​c.3979-9_3979-8dupCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.275
• Publications: 5 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):

• MYH-6 related congenital heart defects

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 14-23389062-A-AGG is Benign according to our data. Variant chr14-23389062-A-AGG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 928727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.3979-9_3979-8dupCC		splice_region intron	N/A	NP_002462.2	P13533

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3979-8_3979-7insCC		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-8_4012-7insCC		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-8_3979-7insCC		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0000259 AC: 3 AN: 115624 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000329

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000427

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 27 AN: 1059776 Hom.: 0 Cov.: 0 AF XY: 0.0000208 AC XY: 11 AN XY: 528120

⚠️ 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: 30388

American (AMR) AF: 0.0000338 AC: 1 AN: 29556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19388

East Asian (EAS) AF: 0.0000360 AC: 1 AN: 27796

South Asian (SAS) AF: 0.0000458 AC: 3 AN: 65522

European-Finnish (FIN) AF: 0.0000286 AC: 1 AN: 35024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4192

European-Non Finnish (NFE) AF: 0.0000212 AC: 17 AN: 802756

Other (OTH) AF: 0.0000886 AC: 4 AN: 45154

⚠️ 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 AF: 0.0000259 AC: 3 AN: 115624 Hom.: 0 Cov.: 0 AF XY: 0.0000176 AC XY: 1 AN XY: 56768

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

African (AFR) AF: 0.00 AC: 0 AN: 38780

American (AMR) AF: 0.00 AC: 0 AN: 11278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2598

East Asian (EAS) AF: 0.000329 AC: 1 AN: 3042

South Asian (SAS) AF: 0.00 AC: 0 AN: 3432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.0000427 AC: 2 AN: 46892

Other (OTH) AF: 0.00 AC: 0 AN: 1568

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28

Splicing

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

Other links and lift over

dbSNP: rs193922652; hg19: chr14-23858271;