NM_002471.4:c.3979-10C>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):​c.3979-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 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 0.00039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00032 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 intron
• Scores: Splicing: ADA: 0.01427
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-23389065-G-T is Benign according to our data. Variant chr14-23389065-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000388 (48/123664) while in subpopulation AMR AF = 0.000902 (12/13308). AF 95% confidence interval is 0.00052. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 48 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>A		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>A		intron	N/A	ENSP00000386041.3
	MYH6	ENST00000968262.1		c.4012-10C>A		intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-10C>A		intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 48 AN: 123556 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.000886

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000395

Gnomad OTH AF: 0.000575

GnomAD2 exomes AF: 0.000409 AC: 78 AN: 190566 AF XY: 0.000499

Gnomad AFR exome AF: 0.0000881

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000660

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000317 AC: 447 AN: 1408692 Hom.: 4 Cov.: 36 AF XY: 0.000343 AC XY: 240 AN XY: 699514

African (AFR) AF: 0.0000608 AC: 2 AN: 32906

American (AMR) AF: 0.000417 AC: 18 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24728

East Asian (EAS) AF: 0.00112 AC: 44 AN: 39238

South Asian (SAS) AF: 0.000601 AC: 50 AN: 83172

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47796

Middle Eastern (MID) AF: 0.000546 AC: 3 AN: 5490

European-Non Finnish (NFE) AF: 0.000290 AC: 311 AN: 1073780

Other (OTH) AF: 0.000308 AC: 18 AN: 58376

GnomAD4 genome AF: 0.000388 AC: 48 AN: 123664 Hom.: 0 Cov.: 30 AF XY: 0.000395 AC XY: 24 AN XY: 60728

African (AFR) AF: 0.000180 AC: 6 AN: 33384

American (AMR) AF: 0.000902 AC: 12 AN: 13308

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

East Asian (EAS) AF: 0.000587 AC: 3 AN: 5114

South Asian (SAS) AF: 0.000887 AC: 4 AN: 4510

European-Finnish (FIN) AF: 0.000112 AC: 1 AN: 8906

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

European-Non Finnish (NFE) AF: 0.000395 AC: 21 AN: 53148

Other (OTH) AF: 0.000568 AC: 1 AN: 1762

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.6
DANN	Benign	0.87
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.0		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;