rs2627037

Variant names:

• chr2-178741811-G-A
• rs2627037
• NM_001267550.2:c.11422C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178741811-G-A
• chr2-178741811-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.11422C>T​(p.Pro3808Ser) variant causes a missense change. The variant allele was found at a frequency of 0.117 in 1,612,258 control chromosomes in the GnomAD database, including 19,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4958 hom., cov: 32)
  • Exomes 𝑓: 0.11 (14532 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.37
• Publications: 34 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003395766).
• BP6: Variant 2-178741811-G-A is Benign according to our data. Variant chr2-178741811-G-A is described in ClinVar as Benign. ClinVar VariationId is 47807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

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.11422C>T	p.Pro3808Ser	missense	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10471C>T	p.Pro3491Ser	missense	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.10909C>T	p.Pro3637Ser	missense	Exon 46 of 192	NP_597681.4	A0A0A0MRA3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11422C>T	p.Pro3808Ser	missense	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11422C>T	p.Pro3808Ser	missense	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11146C>T	p.Pro3716Ser	missense	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31031 AN: 151746 Hom.: 4913 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.182 AC: 44798 AN: 246178 AF XY: 0.166

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.108 AC: 157457 AN: 1460394 Hom.: 14532 Cov.: 33 AF XY: 0.108 AC XY: 78307 AN XY: 726436

African (AFR) AF: 0.429 AC: 14339 AN: 33440

American (AMR) AF: 0.434 AC: 19283 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2689 AN: 26106

East Asian (EAS) AF: 0.201 AC: 7960 AN: 39530

South Asian (SAS) AF: 0.206 AC: 17709 AN: 86146

European-Finnish (FIN) AF: 0.113 AC: 6034 AN: 53304

Middle Eastern (MID) AF: 0.0905 AC: 521 AN: 5760

European-Non Finnish (NFE) AF: 0.0732 AC: 81300 AN: 1111338

Other (OTH) AF: 0.126 AC: 7622 AN: 60302

GnomAD4 genome AF: 0.205 AC: 31138 AN: 151864 Hom.: 4958 Cov.: 32 AF XY: 0.210 AC XY: 15567 AN XY: 74224

African (AFR) AF: 0.417 AC: 17256 AN: 41396

American (AMR) AF: 0.314 AC: 4782 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.212 AC: 1088 AN: 5142

South Asian (SAS) AF: 0.213 AC: 1025 AN: 4812

European-Finnish (FIN) AF: 0.109 AC: 1157 AN: 10568

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0740 AC: 5026 AN: 67930

Other (OTH) AF: 0.167 AC: 352 AN: 2106

Alfa AF: 0.117 Hom.: 7476

Bravo AF: 0.233

TwinsUK AF: 0.0725 AC: 269

ALSPAC AF: 0.0752 AC: 290

ESP6500AA AF: 0.421 AC: 1541

ESP6500EA AF: 0.0732 AC: 597

ExAC AF: 0.174 AC: 21049

Asia WGS AF: 0.217 AC: 751 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.95
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.98	T
PhyloP100		4.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.16
Sift	Benign	0.76	T
Vest4		0.040
MPC		0.084
ClinPred		0.0058	T
GERP RS		6.1
Mutation Taster		=73/27	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: rs2627037; hg19: chr2-179606538; COSMIC: COSV59946576; COSMIC: COSV59946576;