18-49929553-C-T

Variant names:

• chr18-49929553-C-T
• rs2298628
• NM_001080467.3:c.2049G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001080467.3(MYO5B):​c.2049G>A​(p.Val683Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,605,794 control chromosomes in the GnomAD database, including 226,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18337 hom., cov: 26)
  • Exomes 𝑓: 0.53 (208650 hom.)
• Consequence: MYO5B NM_001080467.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.208
• Publications: 15 publications found

Genes affected

MYO5B (HGNC:7603): (myosin VB) The protein encoded by this gene, together with other proteins, may be involved in plasma membrane recycling. Mutations in this gene are associated with microvillous inclusion disease. [provided by RefSeq, Sep 2009]

MYO5B Gene-Disease associations (from GenCC):

• microvillus inclusion disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• cholestasis, progressive familial intrahepatic, 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial intrahepatic cholestasis type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 18-49929553-C-T is Benign according to our data. Variant chr18-49929553-C-T is described in ClinVar as Benign. ClinVar VariationId is 327053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.208 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080467.3. 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
	MYO5B	NM_001080467.3	MANE Select	c.2049G>A	p.Val683Val	synonymous	Exon 17 of 40	NP_001073936.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	ENST00000285039.12	TSL:1 MANE Select	c.2049G>A	p.Val683Val	synonymous	Exon 17 of 40	ENSP00000285039.6
	MYO5B	ENST00000697219.1		c.1845G>A	p.Val615Val	synonymous	Exon 15 of 38	ENSP00000513188.1
	MYO5B	ENST00000908785.1		c.2049G>A	p.Val683Val	synonymous	Exon 17 of 28	ENSP00000578844.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 72853 AN: 149870 Hom.: 18340 Cov.: 26

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.504

GnomAD2 exomes AF: 0.468 AC: 114072 AN: 243844 AF XY: 0.480

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.589

Gnomad EAS exome AF: 0.239

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.530 AC: 771611 AN: 1455804 Hom.: 208650 Cov.: 50 AF XY: 0.531 AC XY: 384048 AN XY: 723786

African (AFR) AF: 0.409 AC: 13652 AN: 33386

American (AMR) AF: 0.325 AC: 14463 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 15337 AN: 26066

East Asian (EAS) AF: 0.261 AC: 10360 AN: 39676

South Asian (SAS) AF: 0.473 AC: 40470 AN: 85520

European-Finnish (FIN) AF: 0.456 AC: 23746 AN: 52018

Middle Eastern (MID) AF: 0.571 AC: 2450 AN: 4292

European-Non Finnish (NFE) AF: 0.559 AC: 620368 AN: 1110246

Other (OTH) AF: 0.512 AC: 30765 AN: 60116

GnomAD4 genome AF: 0.486 AC: 72862 AN: 149990 Hom.: 18337 Cov.: 26 AF XY: 0.481 AC XY: 35166 AN XY: 73064

African (AFR) AF: 0.411 AC: 16715 AN: 40650

American (AMR) AF: 0.408 AC: 6143 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2032 AN: 3460

East Asian (EAS) AF: 0.252 AC: 1282 AN: 5088

South Asian (SAS) AF: 0.458 AC: 2164 AN: 4730

European-Finnish (FIN) AF: 0.475 AC: 4763 AN: 10026

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 37893 AN: 67688

Other (OTH) AF: 0.500 AC: 1043 AN: 2086

Alfa AF: 0.529 Hom.: 28700

Bravo AF: 0.473

Asia WGS AF: 0.380 AC: 1324 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Congenital microvillous atrophy (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.6
DANN	Benign	0.75
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2298628; hg19: chr18-47455923; COSMIC: COSV53217506;