rs2301354

Positions:

• chr17-41487394-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003771.5(KRT36):​c.944C>T​(p.Thr315Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,612,810 control chromosomes in the GnomAD database, including 240,108 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (19674 hom., cov: 33)
  • Exomes 𝑓: 0.55 (220434 hom.)
• Consequence: KRT36 NM_003771.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.646

Genes affected

KRT36 (HGNC:6454): (keratin 36) The protein encoded by this gene is a member of the keratin gene family. This type I hair keratin is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.09239E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT36	NM_003771.5	c.944C>T	p.Thr315Met	missense_variant	5/7	ENST00000328119.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT36	ENST00000328119.11	c.944C>T	p.Thr315Met	missense_variant	5/7	2	NM_003771.5	P1
KRT36	ENST00000393986.2	c.794C>T	p.Thr265Met	missense_variant	6/8	1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76389 AN: 151988 Hom.: 19663 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.519

GnomAD3 exomes AF: 0.546 AC: 136215 AN: 249640 Hom.: 38026 AF XY: 0.553 AC XY: 74651 AN XY: 134964

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.349

Gnomad SAS exome AF: 0.665

Gnomad FIN exome AF: 0.529

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.546 AC: 798076 AN: 1460706 Hom.: 220434 Cov.: 60 AF XY: 0.551 AC XY: 400237 AN XY: 726618

Gnomad4 AFR exome AF: 0.394

Gnomad4 AMR exome AF: 0.581

Gnomad4 ASJ exome AF: 0.553

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.662

Gnomad4 FIN exome AF: 0.533

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.539

GnomAD4 genome AF: 0.502 AC: 76428 AN: 152104 Hom.: 19674 Cov.: 33 AF XY: 0.501 AC XY: 37228 AN XY: 74372

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.515

Alfa AF: 0.538 Hom.: 41277

Bravo AF: 0.498

TwinsUK AF: 0.550 AC: 2039

ALSPAC AF: 0.563 AC: 2170

ESP6500AA AF: 0.414 AC: 1824

ESP6500EA AF: 0.547 AC: 4702

ExAC AF: 0.547 AC: 66386

Asia WGS AF: 0.479 AC: 1667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.000091	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.82	P;.
Vest4		0.070
MPC		0.70
ClinPred		0.055	T
GERP RS		1.1
Varity_R		0.40
gMVP		0.39

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: rs2301354; hg19: chr17-39643646; COSMIC: COSV60202614;