rs187925021

Variant names:

• chr2-178723228-G-T
• rs187925021
• NM_001267550.2:c.21779C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178723228-G-T
• chr2-178723228-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.21779C>A​(p.Ser7260Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,613,574 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (57 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 4.03
• Publications: 7 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]

ENSG00000267784 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070914924).
• BP6: Variant 2-178723228-G-T is Benign according to our data. Variant chr2-178723228-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00207 (315/152240) while in subpopulation SAS AF = 0.029 (140/4824). AF 95% confidence interval is 0.0251. There are 5 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.21779C>A	p.Ser7260Tyr	missense	Exon 75 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.20828C>A	p.Ser6943Tyr	missense	Exon 73 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.18047C>A	p.Ser6016Tyr	missense	Exon 72 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.21779C>A	p.Ser7260Tyr	missense	Exon 75 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.21779C>A	p.Ser7260Tyr	missense	Exon 75 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.21503C>A	p.Ser7168Tyr	missense	Exon 73 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152122 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00395 AC: 978 AN: 247774 AF XY: 0.00504

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00198 AC: 2889 AN: 1461334 Hom.: 57 Cov.: 33 AF XY: 0.00269 AC XY: 1957 AN XY: 726940

African (AFR) AF: 0.00242 AC: 81 AN: 33450

American (AMR) AF: 0.00107 AC: 48 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.0268 AC: 2312 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1111666

Other (OTH) AF: 0.00268 AC: 162 AN: 60340

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152240 Hom.: 5 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74418

African (AFR) AF: 0.00257 AC: 107 AN: 41564

American (AMR) AF: 0.00151 AC: 23 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0290 AC: 140 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68002

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000861 Hom.: 1

Bravo AF: 0.00169

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00161 AC: 6

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.00445 AC: 538

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.86
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.67	T
PhyloP100		4.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.028	D
Polyphen		0.0	B
Vest4		0.41
MVP		0.59
MPC		0.11
ClinPred		0.013	T
GERP RS		5.8
Mutation Taster		=92/8	polymorphism

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: rs187925021; hg19: chr2-179587955;