2-191390479-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001130158.3(MYO1B):c.1969A>C(p.Lys657Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,254 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 Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MYO1B NM_001130158.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37

Genes affected

MYO1B (HGNC:7596): (myosin IB) Enables ATP binding activity; actin filament binding activity; and microfilament motor activity. Involved in actin filament organization and post-Golgi vesicle-mediated transport. Located in several cellular components, including actin filament; endosome; and perinuclear region of cytoplasm. Colocalizes with trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYO1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.32048208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1B	NM_001130158.3	c.1969A>C	p.Lys657Gln	missense_variant	18/31	ENST00000392318.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1B	ENST00000392318.8	c.1969A>C	p.Lys657Gln	missense_variant	18/31	1	NM_001130158.3	P1
MYO1B	ENST00000304164.8	c.1969A>C	p.Lys657Gln	missense_variant	18/31	1		P1
MYO1B	ENST00000339514.8	c.1969A>C	p.Lys657Gln	missense_variant	18/29	1
MYO1B	ENST00000392316.5	c.1969A>C	p.Lys657Gln	missense_variant	17/29	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33

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.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The c.1969A>C (p.K657Q) alteration is located in exon 18 (coding exon 17) of the MYO1B gene. This alteration results from a A to C substitution at nucleotide position 1969, causing the lysine (K) at amino acid position 657 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	0.038
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.039	B;B;B;.
Vest4		0.43
MutPred		0.39		Loss of methylation at K657 (P = 0.0065);Loss of methylation at K657 (P = 0.0065);Loss of methylation at K657 (P = 0.0065);Loss of methylation at K657 (P = 0.0065);
MVP		0.57
MPC		0.53
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs754453637; hg19: chr2-192255205;