14-23389065-G-C

Variant names:

• chr14-23389065-G-C
• rs28730768
• NM_002471.4:c.3979-10C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002471.4(MYH6):​c.3979-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 123,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 intron
• Scores: Splicing: ADA: 0.002426
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-23389065-G-C is Benign according to our data. Variant chr14-23389065-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 19 AD gene.

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.3979-10C>G		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.3979-10C>G		intron	N/A	ENSP00000386041.3
	MYH6	ENST00000968262.1		c.4012-10C>G		intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-10C>G		intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000146 AC: 18 AN: 123556 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000665

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000241 AC: 46 AN: 190566 AF XY: 0.000298

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000335

Gnomad FIN exome AF: 0.000136

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000175 AC: 246 AN: 1408680 Hom.: 0 Cov.: 36 AF XY: 0.000209 AC XY: 146 AN XY: 699506

African (AFR) AF: 0.000152 AC: 5 AN: 32906

American (AMR) AF: 0.000255 AC: 11 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24730

East Asian (EAS) AF: 0.000561 AC: 22 AN: 39238

South Asian (SAS) AF: 0.000890 AC: 74 AN: 83176

European-Finnish (FIN) AF: 0.0000418 AC: 2 AN: 47796

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5490

European-Non Finnish (NFE) AF: 0.000117 AC: 126 AN: 1073764

Other (OTH) AF: 0.0000685 AC: 4 AN: 58374

GnomAD4 genome AF: 0.000154 AC: 19 AN: 123664 Hom.: 0 Cov.: 30 AF XY: 0.000165 AC XY: 10 AN XY: 60728

African (AFR) AF: 0.000210 AC: 7 AN: 33384

American (AMR) AF: 0.0000751 AC: 1 AN: 13308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2528

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5114

South Asian (SAS) AF: 0.000665 AC: 3 AN: 4510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53148

Other (OTH) AF: 0.00 AC: 0 AN: 1762

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	MYH6-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.8
DANN	Benign	0.72
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.078
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: rs28730768; hg19: chr14-23858274;