19-50210398-G-C

Variant names:

• chr19-50210398-G-C
• rs8106196
• NM_001145809.2:c.33G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145809.2(MYH14):​c.33G>C​(p.Arg11Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,580,478 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (100 hom., cov: 32)
  • Exomes 𝑓: 0.027 (630 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.62
• Publications: 3 publications found

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-50210398-G-C is Benign according to our data. Variant chr19-50210398-G-C is described in ClinVar as Benign. ClinVar VariationId is 44065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.62 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. 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
	MYH14	NM_001145809.2	MANE Select	c.33G>C	p.Arg11Arg	synonymous	Exon 2 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.33G>C	p.Arg11Arg	synonymous	Exon 2 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.33G>C	p.Arg11Arg	synonymous	Exon 2 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.33G>C	p.Arg11Arg	synonymous	Exon 2 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.33G>C	p.Arg11Arg	synonymous	Exon 2 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.33G>C	p.Arg11Arg	synonymous	Exon 2 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4806 AN: 152122 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0312

GnomAD2 exomes AF: 0.0241 AC: 4594 AN: 190242 AF XY: 0.0245

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0498

Gnomad EAS exome AF: 0.0000704

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0271 AC: 38679 AN: 1428238 Hom.: 630 Cov.: 31 AF XY: 0.0269 AC XY: 19053 AN XY: 708706

African (AFR) AF: 0.0542 AC: 1673 AN: 30854

American (AMR) AF: 0.0150 AC: 620 AN: 41468

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 1276 AN: 25314

East Asian (EAS) AF: 0.0000806 AC: 3 AN: 37200

South Asian (SAS) AF: 0.0153 AC: 1254 AN: 81956

European-Finnish (FIN) AF: 0.0291 AC: 1450 AN: 49818

Middle Eastern (MID) AF: 0.0490 AC: 279 AN: 5692

European-Non Finnish (NFE) AF: 0.0277 AC: 30412 AN: 1097134

Other (OTH) AF: 0.0291 AC: 1712 AN: 58802

GnomAD4 genome AF: 0.0316 AC: 4814 AN: 152240 Hom.: 100 Cov.: 32 AF XY: 0.0319 AC XY: 2377 AN XY: 74460

African (AFR) AF: 0.0480 AC: 1997 AN: 41576

American (AMR) AF: 0.0188 AC: 287 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.0163 AC: 79 AN: 4832

European-Finnish (FIN) AF: 0.0283 AC: 300 AN: 10598

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0271 AC: 1845 AN: 67988

Other (OTH) AF: 0.0308 AC: 65 AN: 2108

Alfa AF: 0.0226 Hom.: 20

Bravo AF: 0.0317

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		1.6
PromoterAI		-0.089	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs8106196; hg19: chr19-50713655;