12-52949280-A-C

Position:

• chr12-52949280-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP3 BS2

The ENST00000388835.4(KRT18):​c.107A>C​(p.Tyr36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,458,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 40)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KRT18 ENST00000388835.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

KRT18 (HGNC:6430): (keratin 18) KRT18 encodes the type I intermediate filament chain keratin 18. Keratin 18, together with its filament partner keratin 8, are perhaps the most commonly found members of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

KRT8 (HGNC:6446): (keratin 8) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a modified_residue Phosphotyrosine (size 0) in uniprot entity K1C18_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT18	NM_000224.3	c.107A>C	p.Tyr36Ser	missense_variant	1/7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.107A>C	p.Tyr36Ser	missense_variant	2/8		NP_954657.1
KRT8	NM_001256293.2	c.-47+435T>G		intron_variant			NP_001243222.1
KRT8	NR_045962.2	n.405+176T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.107A>C	p.Tyr36Ser	missense_variant	1/7	1	NM_000224.3	ENSP00000373487	P1

Frequencies

GnomAD3 genomes Cov.: 40

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243828 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458444 Hom.: 0 Cov.: 36 AF XY: 0.0000207 AC XY: 15 AN XY: 725544

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome Cov.: 40

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.107A>C (p.Y36S) alteration is located in exon 1 (coding exon 1) of the KRT18 gene. This alteration results from a A to C substitution at nucleotide position 107, causing the tyrosine (Y) at amino acid position 36 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;.;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.069	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.95	P;P;P
Vest4		0.54
MutPred		0.42		Gain of catalytic residue at G40 (P = 0);Gain of catalytic residue at G40 (P = 0);Gain of catalytic residue at G40 (P = 0);
MVP		0.82
MPC		1.4
ClinPred		0.97	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs891346528; hg19: chr12-53343064;