rs116592778

Variant names:

• chr2-178592954-A-G
• rs116592778
• NM_001267550.2:c.59165T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178592954-A-G
• chr2-178592954-A-C

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.59165T>C​(p.Val19722Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000704 in 1,613,478 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.77
• Publications: 8 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=0.0077962577).
• BP6: Variant 2-178592954-A-G is Benign according to our data. Variant chr2-178592954-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00383 (582/152116) while in subpopulation AFR AF = 0.0132 (547/41526). AF 95% confidence interval is 0.0123. There are 3 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.59165T>C	p.Val19722Ala	missense	Exon 300 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.54242T>C	p.Val18081Ala	missense	Exon 250 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.51461T>C	p.Val17154Ala	missense	Exon 249 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.59165T>C	p.Val19722Ala	missense	Exon 300 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.59009T>C	p.Val19670Ala	missense	Exon 298 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.58889T>C	p.Val19630Ala	missense	Exon 298 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 579 AN: 151998 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.000970 AC: 241 AN: 248466 AF XY: 0.000571

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000890

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000379 AC: 554 AN: 1461362 Hom.: 2 Cov.: 35 AF XY: 0.000319 AC XY: 232 AN XY: 726970

African (AFR) AF: 0.0127 AC: 424 AN: 33450

American (AMR) AF: 0.000693 AC: 31 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111638

Other (OTH) AF: 0.000928 AC: 56 AN: 60356

GnomAD4 genome AF: 0.00383 AC: 582 AN: 152116 Hom.: 3 Cov.: 32 AF XY: 0.00358 AC XY: 266 AN XY: 74326

African (AFR) AF: 0.0132 AC: 547 AN: 41526

American (AMR) AF: 0.00118 AC: 18 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67966

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00119 Hom.: 3

Bravo AF: 0.00419

ESP6500AA AF: 0.0110 AC: 42

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00127 AC: 153

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.85
Eigen	Benign	-0.15
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N
PhyloP100		5.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.52
MVP		0.34
MPC		0.10
ClinPred		0.027	T
GERP RS		5.0
Mutation Taster		=94/6	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: rs116592778; hg19: chr2-179457681; COSMIC: COSV104644706; COSMIC: COSV104644706;