chr19-50223085-C-G

Variant names:

• chr19-50223085-C-G
• rs200818171
• NM_001145809.2:c.565C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145809.2(MYH14):​c.565C>G​(p.Arg189Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MYH14 NM_001145809.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.565C>G	p.Arg189Gly	missense_variant, splice_region_variant	Exon 4 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.565C>G	p.Arg189Gly	missense_variant, splice_region_variant	Exon 4 of 42		NP_001070654.1
MYH14	NM_024729.4	c.565C>G	p.Arg189Gly	missense_variant, splice_region_variant	Exon 4 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.565C>G	p.Arg189Gly	missense_variant, splice_region_variant	Exon 4 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;.;D;.;D;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;D;D;.;D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Benign	1.7	L;L;L;L;.;L;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.4	.;D;D;.;.;.;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	.;D;D;.;.;.;.
Sift4G	Uncertain	0.015	D;D;D;.;T;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.79
MutPred		0.69		Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);
MVP		0.66
MPC		1.5
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.52
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200818171; hg19: chr19-50726342;