chr2-178580041-C-G

Variant names:

• chr2-178580041-C-G
• rs4145333
• NM_001267550.2:c.67246G>C

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.67246G>C​(p.Ala22416Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,613,358 control chromosomes in the GnomAD database, including 805,230 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22416T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 1.0 (75484 hom., cov: 32)
  • Exomes 𝑓: 1.0 (729746 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.887
• 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]

ENSG00000270574 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.901181E-7).
• BP6: Variant 2-178580041-C-G is Benign according to our data. Variant chr2-178580041-C-G is described in ClinVar as Benign. ClinVar VariationId is 47250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.993 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.67246G>C	p.Ala22416Pro	missense	Exon 318 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.62323G>C	p.Ala20775Pro	missense	Exon 268 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.59542G>C	p.Ala19848Pro	missense	Exon 267 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.67246G>C	p.Ala22416Pro	missense	Exon 318 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.67090G>C	p.Ala22364Pro	missense	Exon 316 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.66970G>C	p.Ala22324Pro	missense	Exon 316 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.996 AC: 151443 AN: 152048 Hom.: 75426 Cov.: 32

Gnomad AFR AF: 0.986

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.998

GnomAD2 exomes AF: 0.999 AC: 248241 AN: 248558 AF XY: 0.999

Gnomad AFR exome AF: 0.985

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1460338 AN: 1461192 Hom.: 729746 Cov.: 65 AF XY: 0.999 AC XY: 726519 AN XY: 726890

African (AFR) AF: 0.985 AC: 32918 AN: 33432

American (AMR) AF: 0.999 AC: 44658 AN: 44708

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26118 AN: 26118

East Asian (EAS) AF: 1.00 AC: 39662 AN: 39662

South Asian (SAS) AF: 1.00 AC: 86240 AN: 86242

European-Finnish (FIN) AF: 1.00 AC: 53398 AN: 53398

Middle Eastern (MID) AF: 0.998 AC: 5746 AN: 5756

European-Non Finnish (NFE) AF: 1.00 AC: 1111322 AN: 1111532

Other (OTH) AF: 0.999 AC: 60276 AN: 60344

GnomAD4 genome AF: 0.996 AC: 151560 AN: 152166 Hom.: 75484 Cov.: 32 AF XY: 0.996 AC XY: 74091 AN XY: 74372

African (AFR) AF: 0.987 AC: 40997 AN: 41558

American (AMR) AF: 0.999 AC: 15253 AN: 15272

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5125 AN: 5126

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67956 AN: 67974

Other (OTH) AF: 0.998 AC: 2110 AN: 2114

Alfa AF: 0.963 Hom.: 53521

Bravo AF: 0.995

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.986 AC: 3778

ESP6500EA AF: 1.00 AC: 8261

ExAC AF: 0.999 AC: 120644

Asia WGS AF: 1.00 AC: 3477 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	13	not specified (13)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.80
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.89
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.10
Sift	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.11
ClinPred		0.00030	T
GERP RS		1.8
Mutation Taster		=100/0	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: rs4145333; hg19: chr2-179444768; COSMIC: COSV104640673; COSMIC: COSV104640673;