rs373345984

Variant names:

• chr14-23390309-G-A
• rs373345984
• NM_002471.4:c.3480C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23390309-G-A
• chr14-23390309-G-C
• chr14-23390309-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002471.4(MYH6):​c.3480C>T​(p.Ser1160Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,606,070 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (24 hom., cov: 31)
  • Exomes 𝑓: 0.00095 (20 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.09
• 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):

• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 14-23390309-G-A is Benign according to our data. Variant chr14-23390309-G-A is described in ClinVar as Benign. ClinVar VariationId is 44486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (1271/151266) while in subpopulation AFR AF = 0.0294 (1211/41144). AF 95% confidence interval is 0.0281. There are 24 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1271 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.3480C>T	p.Ser1160Ser	synonymous	Exon 26 of 39	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.3480C>T	p.Ser1160Ser	synonymous	Exon 26 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3513C>T	p.Ser1171Ser	synonymous	Exon 26 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3480C>T	p.Ser1160Ser	synonymous	Exon 26 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1268 AN: 151148 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000885

Gnomad OTH AF: 0.00580

GnomAD2 exomes AF: 0.00220 AC: 520 AN: 236738 AF XY: 0.00157

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000854

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.000947 AC: 1378 AN: 1454804 Hom.: 20 Cov.: 34 AF XY: 0.000756 AC XY: 547 AN XY: 723812

African (AFR) AF: 0.0317 AC: 1057 AN: 33352

American (AMR) AF: 0.00203 AC: 90 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000116 AC: 10 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50830

Middle Eastern (MID) AF: 0.00187 AC: 8 AN: 4286

European-Non Finnish (NFE) AF: 0.0000892 AC: 99 AN: 1110296

Other (OTH) AF: 0.00190 AC: 114 AN: 60008

GnomAD4 genome AF: 0.00840 AC: 1271 AN: 151266 Hom.: 24 Cov.: 31 AF XY: 0.00794 AC XY: 587 AN XY: 73898

African (AFR) AF: 0.0294 AC: 1211 AN: 41144

American (AMR) AF: 0.00270 AC: 41 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000885 AC: 6 AN: 67810

Other (OTH) AF: 0.00574 AC: 12 AN: 2092

Alfa AF: 0.00397 Hom.: 1

Bravo AF: 0.00970

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.3
DANN	Benign	0.92
PhyloP100		-3.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373345984; hg19: chr14-23859518;