2-178702613-G-A

Variant names:

• chr2-178702613-G-A
• rs72650011
• NM_001267550.2:c.30274C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.30274C>T​(p.His10092Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00349 in 1,613,946 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:20
• Conservation: PhyloP100: 5.75
• Publications: 12 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008301914).
• BP6: Variant 2-178702613-G-A is Benign according to our data. Variant chr2-178702613-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46832.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00361 (549/152248) while in subpopulation NFE AF = 0.00559 (380/68012). AF 95% confidence interval is 0.00512. There are 2 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.30274C>T	p.His10092Tyr	missense	Exon 107 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.29323C>T	p.His9775Tyr	missense	Exon 105 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26542C>T	p.His8848Tyr	missense	Exon 104 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.30274C>T	p.His10092Tyr	missense	Exon 107 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.30274C>T	p.His10092Tyr	missense	Exon 107 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.29998C>T	p.His10000Tyr	missense	Exon 105 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 549 AN: 152128 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00382 AC: 951 AN: 249204 AF XY: 0.00395

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00965

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00347 AC: 5076 AN: 1461698 Hom.: 15 Cov.: 32 AF XY: 0.00349 AC XY: 2536 AN XY: 727132

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00227 AC: 196 AN: 86256

European-Finnish (FIN) AF: 0.00871 AC: 465 AN: 53402

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00374 AC: 4160 AN: 1111858

Other (OTH) AF: 0.00298 AC: 180 AN: 60374

GnomAD4 genome AF: 0.00361 AC: 549 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74434

African (AFR) AF: 0.000482 AC: 20 AN: 41536

American (AMR) AF: 0.00111 AC: 17 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00559 AC: 380 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00448 Hom.: 6

Bravo AF: 0.00226

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000745 AC: 3

ESP6500EA AF: 0.00407 AC: 34

ExAC AF: 0.00413 AC: 500

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	not specified (9)
-	-	7	not provided (7)
-	-	2	Dilated cardiomyopathy 1G (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Primary dilated cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Benign	0.94
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.83	T
PhyloP100		5.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.42
Sift	Benign	0.077	T
Polyphen		0.0060	B
Vest4		0.70
MVP		0.26
MPC		0.099
ClinPred		0.019	T
GERP RS		5.8
PromoterAI		-0.0079	Neutral
Mutation Taster		=67/33	polymorphism

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: rs72650011; hg19: chr2-179567340;