14-23389062-AGGG-AGGGGG

Position:

• chr14-23389062-AGGG-AGGGGG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_002471.4(MYH6):​c.3979-8_3979-7insCC variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.275

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 14-23389062-A-AGG is Benign according to our data. Variant chr14-23389062-A-AGG is described in ClinVar as [Likely_benign]. Clinvar id is 928727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3979-8_3979-7insCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-8_3979-7insCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000338

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000360

Gnomad4 SAS exome AF: 0.0000458

Gnomad4 FIN exome AF: 0.0000286

Gnomad4 NFE exome AF: 0.0000212

Gnomad4 OTH exome AF: 0.0000886

GnomAD4 genome AF: 0.0000259 AC: 3 AN: 115624 Hom.: 0 Cov.: 0 AF XY: 0.0000176 AC XY: 1 AN XY: 56768

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000329

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000427

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2019

Variant summary: MYH6 c.3979-9_3979-8dupCC alters multiple nucleotides in a repeat Cs region located close to a canonical splice site. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 139674 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3979-9_3979-8dupCC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, several del/dup variants have been found in this region and classified as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922652; hg19: chr14-23858271;