chr2-127631287-G-C

Variant names:

• chr2-127631287-G-C
• rs13025959
• NM_001393586.1:c.5019G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001393586.1(MYO7B):​c.5019G>C​(p.Glu1673Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,611,760 control chromosomes in the GnomAD database, including 31,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1673K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2255 hom., cov: 34)
  • Exomes 𝑓: 0.20 (29597 hom.)
• Consequence: MYO7B NM_001393586.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.24
• Publications: 26 publications found

Genes affected

MYO7B (HGNC:7607): (myosin VIIB) The protein encoded by this gene is found in brush border microvilli of epithelial cells in the intestines and kidneys. The encoded protein is involved in linking protocadherins to the actin cytoskeleton and is essential for proper microvilli function. This protein aids in the accumulation of intermicrovillar adhesion components such as harmonin and ANKS4B, and this accumulation is necessary for normal brush border action. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024333298).
• BP6: Variant 2-127631287-G-C is Benign according to our data. Variant chr2-127631287-G-C is described in ClinVar as [Benign]. Clinvar id is 3055551.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7B	NM_001393586.1	c.5019G>C	p.Glu1673Asp	missense_variant	Exon 37 of 48	ENST00000409816.8	NP_001380515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7B	ENST00000409816.8	c.5019G>C	p.Glu1673Asp	missense_variant	Exon 37 of 48	1	NM_001393586.1	ENSP00000386461.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24208 AN: 152162 Hom.: 2255 Cov.: 34

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.190 AC: 46773 AN: 246006 AF XY: 0.203

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.196 AC: 286109 AN: 1459480 Hom.: 29597 Cov.: 36 AF XY: 0.200 AC XY: 145424 AN XY: 725908

African (AFR) AF: 0.0629 AC: 2105 AN: 33466

American (AMR) AF: 0.112 AC: 4997 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3792 AN: 26094

East Asian (EAS) AF: 0.134 AC: 5301 AN: 39656

South Asian (SAS) AF: 0.314 AC: 27063 AN: 86174

European-Finnish (FIN) AF: 0.221 AC: 11511 AN: 52196

Middle Eastern (MID) AF: 0.192 AC: 1108 AN: 5762

European-Non Finnish (NFE) AF: 0.197 AC: 219009 AN: 1111208

Other (OTH) AF: 0.186 AC: 11223 AN: 60304

GnomAD4 genome AF: 0.159 AC: 24210 AN: 152280 Hom.: 2255 Cov.: 34 AF XY: 0.163 AC XY: 12119 AN XY: 74444

African (AFR) AF: 0.0671 AC: 2788 AN: 41564

American (AMR) AF: 0.145 AC: 2226 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3472

East Asian (EAS) AF: 0.139 AC: 717 AN: 5174

South Asian (SAS) AF: 0.323 AC: 1561 AN: 4832

European-Finnish (FIN) AF: 0.226 AC: 2396 AN: 10612

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.200 AC: 13592 AN: 68000

Other (OTH) AF: 0.173 AC: 366 AN: 2114

Alfa AF: 0.159 Hom.: 765

Bravo AF: 0.143

TwinsUK AF: 0.192 AC: 712

ALSPAC AF: 0.191 AC: 735

ESP6500AA AF: 0.0755 AC: 318

ESP6500EA AF: 0.189 AC: 1605

ExAC AF: 0.192 AC: 23227

Asia WGS AF: 0.261 AC: 904 AN: 3476

EpiCase AF: 0.202

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MYO7B-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;.;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.086	T;T;T
Polyphen		0.85	P;P;.
Vest4		0.36
MutPred		0.25		Loss of phosphorylation at Y1644 (P = 0.1769);Loss of phosphorylation at Y1644 (P = 0.1769);.;
MPC		0.28
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.38
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13025959; hg19: chr2-128388862; COSMIC: COSV67345001; COSMIC: COSV67345001;