2-178741264-G-A

Variant names:

• chr2-178741264-G-A
• rs33971253
• NM_001267550.2:c.11969C>T

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.11969C>T​(p.Pro3990Leu) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,613,806 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.19
• Publications: 18 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=0.0061140656).
• BP6: Variant 2-178741264-G-A is Benign according to our data. Variant chr2-178741264-G-A is described in ClinVar as Benign. ClinVar VariationId is 47814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0064 (974/152288) while in subpopulation NFE AF = 0.0115 (779/68022). AF 95% confidence interval is 0.0108. There are 4 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.11969C>T	p.Pro3990Leu	missense	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.11018C>T	p.Pro3673Leu	missense	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.11456C>T	p.Pro3819Leu	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.11969C>T	p.Pro3990Leu	missense	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11969C>T	p.Pro3990Leu	missense	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11693C>T	p.Pro3898Leu	missense	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00651 AC: 1618 AN: 248430 AF XY: 0.00662

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00293

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00514

GnomAD4 exome AF: 0.0104 AC: 15223 AN: 1461518 Hom.: 99 Cov.: 32 AF XY: 0.0102 AC XY: 7420 AN XY: 727046

African (AFR) AF: 0.00209 AC: 70 AN: 33474

American (AMR) AF: 0.00304 AC: 136 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 109 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86258

European-Finnish (FIN) AF: 0.00398 AC: 212 AN: 53304

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0127 AC: 14125 AN: 1111812

Other (OTH) AF: 0.00868 AC: 524 AN: 60364

GnomAD4 genome AF: 0.00640 AC: 974 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00574 AC XY: 427 AN XY: 74452

African (AFR) AF: 0.00245 AC: 102 AN: 41570

American (AMR) AF: 0.00281 AC: 43 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0115 AC: 779 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00923 Hom.: 18

Bravo AF: 0.00657

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00316 AC: 12

ESP6500EA AF: 0.0118 AC: 97

ExAC AF: 0.00700 AC: 846

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0102

EpiControl AF: 0.00942

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	6	not provided (6)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy;C0039240:Supraventricular tachycardia (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	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.71
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.90	T
PhyloP100		5.2
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.24
Sift	Benign	0.26	T
Vest4		0.28
MVP		0.38
MPC		0.17
ClinPred		0.030	T
GERP RS		5.9
Mutation Taster		=65/35	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: rs33971253; hg19: chr2-179605991;